Fluorination of organic compounds

ABSTRACT

Methods for fluorinating organic compounds utilizing a novel organic reagent are described herein. The invention further discloses the utility of this reagent for incorporation of the 18 F isotope into hydroxyl group-containing organic molecules for PET imaging studies. Preparation of the reagents is described along with isolable intermediate structures from reaction of the reagent with a hydroxyl group-containing organic molecule.

RELATED APPLICATIONS

This application is a national stage filing under 35 U.S.C. § 371 ofinternational PCT application, PCT/US2014/061066, filed Oct. 17, 2014,which claims priority under 35 U.S.C. § 119(e) to U.S. ProvisionalPatent Applications, U.S. Ser. No. 61/892,935 filed Oct. 18, 2013, U.S.Ser. No. 61/895,254 filed Oct. 24, 2013, and U.S. Ser. No. 62/037,418filed Aug. 14, 2014, each of which is incorporated herein by reference.

GOVERNMENT SUPPORT

This invention was made with Government support under grants GM088237and EB013042 awarded by National Institutes of Health. The Governmenthas certain rights in the invention.

FIELD OF THE INVENTION

The invention relates to compounds, compositions, kits, systems, andmethods of fluorinating an organic compound using a fluorinating agent.

BACKGROUND OF INVENTION

Functionalized aryl fluorides are used as pharmaceuticals andagrochemicals, in part due to their favorable pharmacological propertiessuch as increased metabolic stability (see, for example, Müller et al.,Science 2007, 317, 1881-1886; Kirk et al., Org. Process Res. Dev. 2001,41, 443-470; and Jeschke, P. ChemBioChem 2004, 5, 570-589). Arylfluorides also find applications as tracers in positron emissiontomography using the [¹⁸F]isotope (Lasne et al., In Contrast Agents II,2002; Vol. 222, pp 201-258). Fluorine has the highest electronegativity,the highest oxidation potential, and the smallest anionic radius of allelements, each of which complicates carbon-fluorine bond formation whencompared to other carbon-heteroatom bond formations (see, for example,Chambers, R. D., Fluorine in organic chemistry. Oxford: New York, 2004;and Furuya et al., Curr. Opin. Drug Discov. Devel. 2008, 11, 803-819).

SUMMARY OF INVENTION

The invention relates to compounds, compositions, kits, systems, andmethods of fluorinating an organic compound using a fluorinating agent.Besides the vast number of applications of fluorinated organic moleculesbearing the natural ¹⁹F isotope, compounds bearing the radioisotope ¹⁸Fare invaluable as ligands for Positron Emission Tomography (PET). PET isa non-invasive imaging technique used to observe and probe biologicalprocesses in vivo. The non-natural isotope ¹⁸F, which is manufacturedwithin 100 miles of ˜98% of the hospital beds in the US, is theradionucleus of choice for many imaging applications due to itsfavorable half-life of 109 min and its low positron emission energy. Theunnatural isotope ¹⁸F is generated using a cyclotron, either asnucleophilic ¹⁸F-fluoride or as electrophilic ¹⁸F-fluorine gas (¹⁸F—F₂).¹⁸F-fluoride is the preferred source of ¹⁸F due to its high isotopicenrichment, wide availability and ease of use. The low reactivity of¹⁸F⁻ towards arenes renders radiofluorination challenging particularlyfor complex substrates that require mild reaction conditions. Due to the109 min half-life of ¹⁸F the introduction of the radionuclide needs tooccur late-stage in the synthesis of the desired radiotracer to avoidunproductive decay. Currently, positron emission tomography (PET) with¹⁸F is most recognized as a clinical tool for the diagnosis and stagingof cancer.

While simple molecules such as 2-deoxy-2-(¹⁸F)fluoro-D-glucose([¹⁸F]FDG) can be efficiently prepared, structurally more complexmolecules often cannot. The potential biomedical applications of PET forstudying a variety of diseases such as cancer, cardiovascular disease,autoimmunity, neurodegeneration, and psychiatric illness are impeded bythe lack of suitable ¹⁸F-based PET tracers. To find a PET tracer withthe desired in vivo properties, a wide range of candidates commonly haveto be radiolabelled and tested. Due to the lack of robust late-stageradiofluorination reactions currently available, tracer synthesis oftenrequires evaluation of several labeling methods and multistep syntheses.Consequently, a general method that can tolerate a multitude ofstructural elements would severely curtail the development time requiredfor new PET tracers.

Broad access to a variety of ¹⁸F-labeled molecules could transformmolecular imaging aimed at determining pathophysiology of diseases inpre-clinical and clinical research and, ultimately, impact patient carethrough improved diagnostic and prognostic criteria. Moreover, drugdevelopment can be streamlined by employing radiolabeled probe moleculesin phase 0 clinical trials, which reveal drug distribution and real-timepharmacokinetics throughout all tissues of the body.

Nucleophilic substitution chemistry is widely used in PET probesynthesis due to its predictability, operational convenience, andapplicability to aliphatic and aromatic substrates. Electron-rich andmany electron-neutral aromatic substrates, however, do not undergodisplacement, and side reactions plague nucleophilic substitutions atmany hindered or secondary aliphatic centers.

Incorporation into diaryl iodonium salts render aromatic rings activatedtowards nucleophilic attack even if no additional electron-withdrawinggroups are present. A drawback of this approach is the difficultyassociated with the synthesis and purification of diaryliodonium salts;many (particularly acid-sensitive) functional groups are not toleratedunder the synthesis conditions currently available.

An ideal radiofluorination method would meet all of the followingcriteria: non-carrier-added reactions, commercially available, benchstable reagents, readily accessible starting materials, operationallysimple radiolabeling and purification procedures, general applicabilityto aliphatic and aromatic substrates. Currently availableradiofluorination methods fall short of at least one of these goals (seeFIG. 3).

The inventors have previously described a reagent for fluorination (seeFIG. 2). The reagent, known as PhenoFluor®, exhibits exceptionalsubstrate scope and functional group tolerance. The new reagents ofFormula (I) provide access to late-stage fluorination similar toPhenoFluor®, but without the need for additional fluoride, so thatno-carrier-added (nca) reactions become feasible.

The new fluorinating reagent is capable of site-specific substitution ofhydroxyl groups with non-carrier-added ¹⁸F-fluoride in a one-steptransformation. The transformation is metal-free and combines thesubstrate scope of late-stage fluorination with the convenient andbroadly implemented reaction setup of simple displacement chemistry. Theuse of readily available phenols or alcohols as labeling precursorsallows rapid access to new PET probes. Development of this method ofradiofluorination into a fully automated, versatile ¹⁸F-labelingprotocol would considerably streamline tracer development through thesynthesis of desirable PET probes.

The fluorination reagent of Formula (I) stems from development of aradiofluorination reaction that can convert convenient startingmaterials to fluorides using non-carrier-added ¹⁸F-fluoride in astraightforward one-step procedure. Phenols and alcohols can readily besynthesized and purified, and the fluorination method can tolerate awide range of functional groups, including tertiary amines and proticfunctional groups.

Substrates such as estrone, which lack electron-withdrawing activatinggroups, undergo radiofluorination. The ability to introduce ¹⁸F-fluorideinto electron-neutral aromatic substrates (see Examples) sets theproposed transformation apart from nucleophilic aromatic substitutionchemistry. Secondary aliphatic alcohols such as cholesterol, menthol,testosterone, and epiandrosterone yield the corresponding radiolabeledderivatives, in most cases with complete stereocontrol (inversion) aswas established by the inventors through deoxyfluorination withPhenoFluor®. A yield of 25% for the radiofluorination of menthol isparticularly noteworthy (see Experimental section) because mentholcontains a hindered, branched substituent in the β-position to thehydroxyl group, which renders the reaction site sterically crowded;conventional nucleophilic displacement reactions typically affordsignificant amounts of byproducts such as those derived from eliminationas observed for displacement reactions at hindered secondary carbonatoms. Unprotected primary anilines such can be tolerated influorination with reagents of Formula (I).

Purification of the radiolabeled material by HPLC is facile because bothphenol and alcohol starting material have a significantly differentpolarity from the fluorinated product. In addition, radiofluorinationwith reagents of Formula (I) is a metal-free transformation, whichfurther simplifies purification because reaction mixtures can bedirectly concentrated and purified by preparative HPLC. The inventorshave found that radiolabeling with reagents of Formula (I) is a veryclean reaction, with only minimal side product formation: The HPLCUV-trace shows only the starting phenol and urea (urea=deprotonatedI-c).

One embodiment of the present invention provides compounds of Formula(I):

wherein:

D is oxygen or sulfur;

A is hydrogen or a Lewis acid;

Q is an anion;

R¹ and R² are independently selected from the group consisting of C₁₋₆alkyl, C₆₋₁₀ aryl, C₆₋₁₀ aralkyl, 5-10 membered heteroaryl, 5-10membered heteroaralkyl, 4-10 membered heterocyclyl, 4-10 memberedheterocyclylalkyl, 3-10 membered carbocyclyl, and 3-10 memberedcarbocyclylalkyl, each of which is optionally substituted with 0 to 5occurrences of R⁵;

R³ and R⁴ are independently selected from the group consisting ofhydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, nitro, cyano, halo,C₁₋₆ haloalkyl, C₁₋₆ alkoxy, optionally substituted C₆₋₁₀ aryl,optionally substituted C₆₋₁₀ aralkyl, optionally substituted 5-10membered heteroaryl, optionally substituted 4-10 membered heterocyclyl,optionally substituted 3-10 membered carbocyclyl, optionally substituted4-10 membered heterocyclylalkyl, acyl, —NH₂, —NHR⁷, —N(R⁷)₂, —OH, —SH,—SO₂R⁷, —SOR⁷, —SO₂NR⁷ ₂, and —SR⁷;

R⁷ is independently selected from the group consisting of hydrogen,acyl, optionally substituted aliphatic, optionally substitutedcarbocyclyl, optionally substituted heterocyclyl, optionally substitutedaryl, and optionally substituted heteroaryl, or two R⁷ groups are takentogether with their intervening atoms to form an optionally substitutedheterocyclic ring;

R⁵ is independently selected from the group consisting of halo, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy,optionally substituted C₆₋₁₀ aryl, optionally substituted 5-10 memberedheteroaryl, optionally substituted 4-10 membered heterocyclyl,optionally substituted 3-10 membered carbocyclyl, nitro, cyano, acyl,—NH₂, —NHR⁷, —N(R⁷)₂, —OH, —SH, —SO₂R⁷, —SOR⁷, —SO₂NR⁷ ₂, and —SR⁷;

t is the anion charge number, ranging from 1-3;

v is 0-3; and

m is 1-5.

Exemplary compounds of Formula (I) include compounds of Formula (I-c)and Formula (I-d):

In another aspect, the present invention provides compounds representedby Formula (II):

wherein S is an organic substrate.

In certain embodiments, the compound of Formula (II) is a compound ofFormula (II-c)-(II-h):

wherein

each occurrence of R⁸ is independently selected from the groupconsisting of C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, nitro, cyano,halo, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, optionally substituted C₆₋₁₀ aryl,optionally substituted C₆₋₁₀ aralkyl, optionally substituted 5-10membered heteroaryl, optionally substituted 4-10 membered heterocyclyl,optionally substituted 3-10 membered carbocyclyl, optionally substituted4-10 membered heterocyclylalkyl, acyl, —N(R^(8a))₂, —OR^(8a),—CO₂R^(8a), —SO₂R^(8a), —SOR^(8a), —SO₂N(R^(8a))₂, and —SR^(8a);

each occurrence of R⁹ is independently selected from the groupconsisting of C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, nitro, cyano,halo, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, optionally substituted C₆₋₁₀ aryl,optionally substituted C₆₋₁₀ aralkyl, optionally substituted 5-10membered heteroaryl, optionally substituted 4-10 membered heterocyclyl,optionally substituted 3-10 membered carbocyclyl, and optionallysubstituted 4-10 membered heterocyclylalkyl, acyl, —N(R^(9a))₂,—OR^(9a), —CO₂R^(9a), —SO₂R^(9a), —SOR^(9a), —SO₂N(R^(9a))₂, and—SR^(9a);

each occurrence of R^(8a) or R^(9a) is independently selected from thegroup consisting of hydrogen, acyl, optionally substituted aliphatic,optionally substituted carbocyclyl, optionally substituted heterocyclyl,optionally substituted aryl, and optionally substituted heteroaryl, ortwo R^(8a) or R^(9a) groups are taken together with their interveningatoms to form an optionally substituted heterocyclic ring; and

p is 0, 1, 2, or 3.

In another aspect, the present invention provides compounds representedby Formula (V):

In certain embodiments, the fluorine is enriched in the ¹⁸F isotope.

In certain embodiments, the compound of Formula (V) is a compound ofFormula (V-c):

In certain embodiments, the fluorine is enriched in the ¹⁸F isotope.

In another aspect, the present invention provides compounds representedby Formula (VI):

wherein

each occurrence of R⁸ is independently selected from the groupconsisting of C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, nitro, cyano,halo, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, optionally substituted C₆₋₁₀ aryl,optionally substituted C₆₋₁₀ aralkyl, optionally substituted 5-10membered heteroaryl, optionally substituted 4-10 membered heterocyclyl,optionally substituted 3-10 membered carbocyclyl, optionally substituted4-10 membered heterocyclylalkyl, acyl, —N(R^(8a))₂, —OR^(8a),—CO₂R^(8a), —SO₂R^(8a), —SOR^(8a), —SO₂N(R^(8a))₂, and —SR^(8a);

each occurrence of R⁹ is independently selected from the groupconsisting of C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, nitro, cyano,halo, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, optionally substituted C₆₋₁₀ aryl,optionally substituted C₆₋₁₀ aralkyl, optionally substituted 5-10membered heteroaryl, optionally substituted 4-10 membered heterocyclyl,optionally substituted 3-10 membered carbocyclyl, and optionallysubstituted 4-10 membered heterocyclylalkyl, acyl, —N(R^(9a))₂,—OR^(9a), —CO₂R^(9a), —SO₂R^(9a), —SOR^(9a), —SO₂N(R^(9a))₂, and—SR^(9a);

each occurrence of R^(8a) or R^(9a) is independently selected from thegroup consisting of hydrogen, acyl, optionally substituted aliphatic,optionally substituted carbocyclyl, optionally substituted heterocyclyl,optionally substituted aryl, and optionally substituted heteroaryl, ortwo R^(8a) or R^(9a) groups are taken together with their interveningatoms to form an optionally substituted heterocyclic ring; and

p is 0, 1, 2, or 3.

In certain embodiments, the compound of Formula (VI) is a compound ofFormula (VI-c)-(VI-f):

In another aspect, the present invention provides methods of replacing ahydroxyl group on an organic compound with a fluorine atom, the methodcomprising contacting a compound of Formula (I):

with an organic compound under conditions sufficient to fluorinate theorganic compound, thereby providing a fluorinated organic compound.

In certain embodiments, the method comprises contacting a compound ofFormula (I-c):

with an organic compound under conditions sufficient to fluorinate theorganic compound, thereby providing a fluorinated organic compound.

In another aspect, the present invention provides methods of replacing ahydroxyl group of an organic compound with a fluorine atom, the methodcomprising exchanging an anion Q of a compound of Formula (II):

with a fluoride or HF₂ anion. In certain embodiments, the ion exchangereaction is carried out using an anion exchange resin or anion exchangechromatography. In certain embodiments, the fluorine source is enrichedin the ¹⁸F isotope. In certain embodiments, the anion exchange reactionis carried out in aqueous dioxane. In certain embodiments, the resultingintermediate is heated to approximately 110° C. following anionexchange. In certain embodiments, the intermediate is heated forapproximately 5 minutes.

In certain embodiments, the method comprises exchanging the chlorideanion of a compound of Formula (II-e):

with a fluoride or HF₂ anion. In certain embodiments, the ion exchangereaction is carried out using an anion exchange resin or anion exchangechromatography. In certain embodiments, the fluorine source is enrichedin the ¹⁸F isotope. In certain embodiments, the anion exchange reactionis carried out in aqueous dioxane. In certain embodiments, the resultingintermediate is heated to approximately 110° C. following anionexchange. In certain embodiments, the intermediate is heated forapproximately 5 minutes.

In certain embodiments, the method comprises exchanging the phenolateanion of a compound of Formula (II-f):

with a fluoride or HF₂ anion. In certain embodiments, the ion exchangereaction is carried out using an anion exchange resin or anion exchangechromatography. In certain embodiments, the fluorine source is enrichedin the ¹⁸F isotope. In certain embodiments, the anion exchange reactionis carried out in aqueous dioxane. In certain embodiments, the resultingintermediate is heated to approximately 110° C. following anionexchange. In certain embodiments, the intermediate is heated forapproximately 5 minutes.

In another aspect, the present invention is directed to a method ofproducing a compound of Formula (II):

the method comprising contacting a compound of Formula (VI):

with a hydroxyl group-containing organic substrate and exchanging

In another aspect, the present invention is directed to a method ofproducing a compound of Formula (I), the method comprising contacting acompound of Formula (I-e):

with a Brønsted acid, a Lewis acid, or an acid anhydride to produce thecompound of Formula (I).

In another aspect, the present invention provides kits comprising acontainer with a compound described herein. The provided kits may beuseful in a method of the invention. In certain embodiments, the kitfurther includes instructions for using the kit.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the general fluorination reactions accomplished through useof reagents of Formula (I).

FIG. 2 shows the effective fluorination of both challenging aryl andaliphatic hydroxyl groups using PhenoFluor®, a reagent previouslydiscovered by the inventors. Comparison to other fluorinating agents ishighlighted to demonstrate the superiority of PhenoFluor®.

FIG. 3 shows the comparison of several radiofluorination methods where atick marks a positive feature of the respective technique (SM=startingmaterial=labeling precursor, NCA=non-carrier-added,Aliphatic=applicability to aliphatic substrates).

FIG. 4 shows the X-ray structure of (I-c) and a molecule ofdichloromethane. Thermal ellipsoids are drawn at the 50% probabilitylevel; H atoms (except those involved in H-bonding) are omitted forclarity, and the disorder model is depicted using transparentellipsoids.

FIG. 5 shows the X-ray structure of (I-c) and a molecule ofdichloromethane with selected atom labeling scheme. Thermal ellipsoidsare drawn at the 50% probability level; Solvent, disorder, and H atoms(except those involved in H-bonding) are omitted for clarity.

FIG. 6 shows Radio TLC scans for isotopic labeling experiments. FIG. 6Ashows the radio TLC scan for the isotopic labeling experiment withestrone. The position at 60 mm corresponds to the baseline of the TLCplate (¹⁸F-fluoride), the position at 90 mm corresponds to ¹⁸F-estrone(RCY=13%). FIG. 6B shows the radio TLC scan for the isotopic labelingexperiment with testosterone. The position at 60 mm corresponds to thebaseline of the TLC plate (¹⁸F-fluoride), the position at 82 mmcorresponds to ¹⁸F-testosterone. FIG. 6C shows the radio TLC scan forthe isotopic labeling experiment with menthol. The position at 60 mmcorresponds to the baseline of the TLC plate (¹⁸F-Fluoride), theposition at 105 mm corresponds to ¹⁸F-menthol.

FIG. 7 shows fluorination reactions carried out through treatment ofuronium intermediates with exogenous fluorine sources. FIG. 7A showsthat anion methathesis of the uronium does not occur under typicalreaction conditions. Instead, extraneous fluoride converts thebifluoride counteranion to a fluoride counteranion, which proceedsattack the aromatic ring. FIG. 7B shows that uronium triflate isunreactive in the presence of fluoride, since triflate, unlikebifluoride, cannot be converted into a fluoride counteranion.

DEFINITIONS

Definitions of specific functional groups and chemical terms aredescribed in more detail below. The chemical elements are identified inaccordance with the Periodic Table of the Elements, CAS version,Handbook of Chemistry and Physics, 75^(th) Ed., inside cover, andspecific functional groups are generally defined as described therein.Additionally, general principles of organic chemistry, as well asspecific functional moieties and reactivity, are described in ThomasSorrell, Organic Chemistry, University Science Books, Sausalito, 1999;Smith and March, March's Advanced Organic Chemistry, 5^(th) Edition,John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive OrganicTransformations, VCH Publishers, Inc., New York, 1989; and Carruthers,Some Modern Methods of Organic Synthesis, 3^(rd) Edition, CambridgeUniversity Press, Cambridge, 1987.

Compounds described herein can comprise one or more asymmetric centers,and thus can exist in various isomeric forms, e.g., enantiomers and/ordiastereomers. For example, the compounds described herein can be in theform of an individual enantiomer, diastereomer or geometric isomer, orcan be in the form of a mixture of stereoisomers, including racemicmixtures and mixtures enriched in one or more stereoisomer. Isomers canbe isolated from mixtures by methods known to those skilled in the art,including chiral high pressure liquid chromatography (HPLC) and theformation and crystallization of chiral salts; or preferred isomers canbe prepared by asymmetric syntheses. See, for example, Jacques et al.,Enantiomers, Racemates and Resolutions (Wiley Interscience, New York,1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistryof Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables ofResolving Agents and Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ.of Notre Dame Press, Notre Dame, Ind. 1972). The present disclosureadditionally encompasses compounds described herein as individualisomers substantially free of other isomers, and alternatively, asmixtures of various isomers.

It is to be understood that the compounds of the present invention maybe depicted as different tautomers. It should also be understood thatwhen compounds have tautomeric forms, all tautomeric forms are intendedto be included in the scope of the present invention, and the naming ofany compound described herein does not exclude any tautomer form.

Unless otherwise stated, structures depicted herein are also meant toinclude compounds that differ only in the presence of one or moreisotopically enriched atoms. For example, compounds having the presentstructures except for the replacement of hydrogen by deuterium ortritium, replacement of ¹⁹F with ¹⁸F, or the replacement of a carbon bya ¹³C- or ¹⁴C-enriched carbon are within the scope of the disclosure.Such compounds are useful, for example, as analytical tools or probes inbiological assays.

The term “aliphatic,” as used herein, includes both saturated andunsaturated, nonaromatic, straight chain (i.e., unbranched), branched,acyclic, and cyclic (i.e., carbocyclic) hydrocarbons. In certainembodiments, an aliphatic group is optionally substituted with one ormore functional groups. As will be appreciated by one of ordinary skillin the art, “aliphatic” is intended herein to include alkyl, alkenyl,alkynyl, cycloalkyl, and cycloalkenyl moieties.

When a range of values is listed, it is intended to encompass each valueand sub-range within the range. For example “C₁₋₆alkyl” is intended toencompass, C₁, C₂, C₃, C₄, C₅, C₆, C₁₋₆, C₁₋₅, C₁₋₄, C₁₋₃, C₁₋₂, C₂₋₆,C₂₋₅, C₂₋₄, C₂₋₃, C₃₋₆, C₃₋₅, C₃₋₄, C₄₋₆, C₄₋₅, and C₅₋₆ alkyl.

“Alkyl” refers to a radical of a straight-chain or branched saturatedhydrocarbon group having from 1 to 20 carbon atoms (“C₁₋₂₀ alkyl”). Incertain embodiments, an alkyl group has 1 to 10 carbon atoms (“C₁₋₁₀alkyl”). In certain embodiments, an alkyl group has 1 to 9 carbon atoms(“C₁₋₉ alkyl”). In certain embodiments, an alkyl group has 1 to 8 carbonatoms (“C₁₋₈ alkyl”). In certain embodiments, an alkyl group has 1 to 7carbon atoms (“C₁₋₇ alkyl”). In certain embodiments, an alkyl group has1 to 6 carbon atoms (“C₁₋₆ alkyl”). In certain embodiments, an alkylgroup has 1 to 5 carbon atoms (“C₁₋₅ alkyl”). In certain embodiments, analkyl group has 1 to 4 carbon atoms (“C₁₋₄ alkyl”). In certainembodiments, an alkyl group has 1 to 3 carbon atoms (“C₁₋₃ alkyl”). Incertain embodiments, an alkyl group has 1 to 2 carbon atoms (“C₁₋₂alkyl”). In certain embodiments, an alkyl group has 1 carbon atom (“C₁alkyl”). In certain embodiments, an alkyl group has 2 to 6 carbon atoms(“C₂₋₆ alkyl”). Examples of C₁₋₆alkyl groups include methyl (C₁), ethyl(C₂), n-propyl (C₃), isopropyl (C₃), n-butyl (C₄), tert-butyl (C₄),sec-butyl (C₄), iso-butyl (C₄), n-pentyl (C₅), 3-pentanyl (C₅), amyl(C₅), neopentyl (C₅), 3-methyl-2-butanyl (C₅), tertiary amyl (C₅), andn-hexyl (C₆). Additional examples of alkyl groups include n-heptyl (C₇),n-octyl (C₈) and the like. In certain embodiments, each instance of analkyl group is independently optionally substituted, e.g., unsubstituted(an “unsubstituted alkyl”) or substituted (a “substituted alkyl”) withone or more substituents. In certain embodiments, the alkyl group isunsubstituted C₁₋₁₀ alkyl (e.g., —CH₃). In certain embodiments, thealkyl group is substituted C₁₋₁₀ alkyl.

In certain embodiments, an alkyl group is substituted with one or morehalogens. “Perhaloalkyl” is a substituted alkyl group as defined hereinwherein all of the hydrogen atoms are independently replaced by ahalogen, e.g., fluoro, bromo, chloro, or iodo. In certain embodiments,the alkyl moiety has 1 to 8 carbon atoms (“C₁₋₈ perhaloalkyl”). Incertain embodiments, the alkyl moiety has 1 to 6 carbon atoms (“C₁₋₆perhaloalkyl”). In certain embodiments, the alkyl moiety has 1 to 4carbon atoms (“C₁₋₄ perhaloalkyl”). In certain embodiments, the alkylmoiety has 1 to 3 carbon atoms (“C₁₋₃ perhaloalkyl”). In certainembodiments, the alkyl moiety has 1 to 2 carbon atoms (“C₁₋₂perhaloalkyl”). In certain embodiments, all of the hydrogen atoms arereplaced with fluoro. In certain embodiments, all of the hydrogen atomsare replaced with chloro. Examples of perhaloalkyl groups include —CF₃,—CF₂CF₃, —CF₂CF₂CF₃, —CCl₃, —CFCl₂, —CF₂Cl, and the like.

“Alkenyl” refers to a radical of a straight-chain or branchedhydrocarbon group having from 2 to 20 carbon atoms, one or morecarbon-carbon double bonds, and no triple bonds (“C₂₋₂₀ alkenyl”). Incertain embodiments, an alkenyl group has 2 to 10 carbon atoms (“C₂₋₁₀alkenyl”). In certain embodiments, an alkenyl group has 2 to 9 carbonatoms (“C₂₋₉ alkenyl”). In certain embodiments, an alkenyl group has 2to 8 carbon atoms (“C₂₋₈ alkenyl”). In certain embodiments, an alkenylgroup has 2 to 7 carbon atoms (“C₂₋₇ alkenyl”). In certain embodiments,an alkenyl group has 2 to 6 carbon atoms (“C₂₋₆ alkenyl”). In certainembodiments, an alkenyl group has 2 to 5 carbon atoms (“C₂₋₅ alkenyl”).In certain embodiments, an alkenyl group has 2 to 4 carbon atoms (“C₂₋₄alkenyl”). In certain embodiments, an alkenyl group has 2 to 3 carbonatoms (“C₂₋₃ alkenyl”). In certain embodiments, an alkenyl group has 2carbon atoms (“C₂ alkenyl”). The one or more carbon-carbon double bondscan be internal (such as in 2-butenyl) or terminal (such as in1-butenyl). Examples of C₂₋₄ alkenyl groups include ethenyl (C₂),1-propenyl (C₃), 2-propenyl (C₃), 1-butenyl (C₄), 2-butenyl (C₄),butadienyl (C₄), and the like. Examples of C₂₋₆ alkenyl groups includethe aforementioned C₂₋₄ alkenyl groups as well as pentenyl (C₅),pentadienyl (C₅), hexenyl (C₆), and the like. Additional examples ofalkenyl include heptenyl (C₇), octenyl (C₈), octatrienyl (C₈), and thelike. In certain embodiments, each instance of an alkenyl group isindependently optionally substituted, e.g., unsubstituted (an“unsubstituted alkenyl”) or substituted (a “substituted alkenyl”) withone or more substituents. In certain embodiments, the alkenyl group isunsubstituted C₂₋₁₀ alkenyl. In certain embodiments, the alkenyl groupis substituted C₂₋₁₀ alkenyl.

“Alkynyl” refers to a radical of a straight-chain or branchedhydrocarbon group having from 2 to 20 carbon atoms, one or morecarbon-carbon triple bonds, and optionally one or more double bonds(“C₂₋₂₀ alkynyl”). In certain embodiments, an alkynyl group has 2 to 10carbon atoms (“C₂₋₁₀ alkynyl”). In certain embodiments, an alkynyl grouphas 2 to 9 carbon atoms (“C₂₋₉ alkynyl”). In certain embodiments, analkynyl group has 2 to 8 carbon atoms (“C₂₋₈ alkynyl”). In certainembodiments, an alkynyl group has 2 to 7 carbon atoms (“C₂₋₇ alkynyl”).In certain embodiments, an alkynyl group has 2 to 6 carbon atoms (“C₂₋₆alkynyl”). In certain embodiments, an alkynyl group has 2 to 5 carbonatoms (“C₂₋₅ alkynyl”). In certain embodiments, an alkynyl group has 2to 4 carbon atoms (“C₂₋₄ alkynyl”). In certain embodiments, an alkynylgroup has 2 to 3 carbon atoms (“C₂₋₃ alkynyl”). In certain embodiments,an alkynyl group has 2 carbon atoms (“C₂ alkynyl”). The one or morecarbon-carbon triple bonds can be internal (such as in 2-butynyl) orterminal (such as in 1-butynyl). Examples of C₂₋₄ alkynyl groupsinclude, without limitation, ethynyl (C₂), 1-propynyl (C₃), 2-propynyl(C₃), 1-butynyl (C₄), 2-butynyl (C₄), and the like. Examples of C₂₋₆alkenyl groups include the aforementioned C₂₋₄ alkynyl groups as well aspentynyl (C₅), hexynyl (C₆), and the like. Additional examples ofalkynyl include heptynyl (C₇), octynyl (C₈), and the like. In certainembodiments, each instance of an alkynyl group is independentlyoptionally substituted, e.g., unsubstituted (an “unsubstituted alkynyl”)or substituted (a “substituted alkynyl”) with one or more substituents.In certain embodiments, the alkynyl group is unsubstituted C₂₋₁₀alkynyl. In certain embodiments, the alkynyl group is substituted C₂₋₁₀alkynyl.

“Carbocyclyl” or “carbocyclic” refers to a radical of a non-aromaticcyclic hydrocarbon group having from 3 to 10 ring carbon atoms (“C₃₋₁₀carbocyclyl”) and zero heteroatoms in the non-aromatic ring system. Incertain embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms(“C₃₋₈ carbocyclyl”). In certain embodiments, a carbocyclyl group has 3to 6 ring carbon atoms (“C₃₋₆ carbocyclyl”). In certain embodiments, acarbocyclyl group has 3 to 6 ring carbon atoms (“C₃₋₆ carbocyclyl”). Incertain embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms(“C₅₋₁₀ carbocyclyl”). Exemplary C₃₋₆ carbocyclyl groups include,without limitation, cyclopropyl (C₃), cyclopropenyl (C₃), cyclobutyl(C₄), cyclobutenyl (C₄), cyclopentyl (C₅), cyclopentenyl (C₅),cyclohexyl (C₆), cyclohexenyl (C₆), cyclohexadienyl (C₆), and the like.Exemplary C₃₋₈ carbocyclyl groups include, without limitation, theaforementioned C₃₋₆ carbocyclyl groups as well as cycloheptyl (C₇),cycloheptenyl (C₇), cycloheptadienyl (C₇), cycloheptatrienyl (C₇),cyclooctyl (C₈), cyclooctenyl (C₈), bicyclo[2.2.1]heptanyl (C₇),bicyclo[2.2.2]octanyl (C₈), and the like. Exemplary C₃₋₁₀ carbocyclylgroups include, without limitation, the aforementioned C₃₋₈ carbocyclylgroups as well as cyclononyl (C₉), cyclononenyl (C₉), cyclodecyl (C₁₀),cyclodecenyl (C₁₀), octahydro-1H-indenyl (C₉), decahydronaphthalenyl(C₁₀), spiro[4.5]decanyl (C₁₀), and the like. As the foregoing examplesillustrate, in certain embodiments, the carbocyclyl group is eithermonocyclic (“monocyclic carbocyclyl”) or is a fused, bridged orspiro-fused ring system such as a bicyclic system (“bicycliccarbocyclyl”) and can be saturated or can be partially unsaturated.“Carbocyclyl” also includes ring systems wherein the carbocyclyl ring,as defined above, is fused with one or more aryl or heteroaryl groupswherein the point of attachment is on the carbocyclyl ring, and in suchinstances, the number of carbons continue to designate the number ofcarbons in the carbocyclic ring system. In certain embodiments, eachinstance of a carbocyclyl group is independently optionally substituted,e.g., unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a“substituted carbocyclyl”) with one or more substituents. In certainembodiments, the carbocyclyl group is unsubstituted C₃₋₁₀ carbocyclyl.In certain embodiments, the carbocyclyl group is a substituted C₃₋₁₀carbocyclyl.

In certain embodiments, “carbocyclyl” is a monocyclic, saturatedcarbocyclyl group having from 3 to 10 ring carbon atoms (“C₃₋₁₀cycloalkyl”). In certain embodiments, a cycloalkyl group has 3 to 8 ringcarbon atoms (“C₃₋₈cycloalkyl”). In certain embodiments, a cycloalkylgroup has 3 to 6 ring carbon atoms (“C₃₋₆ cycloalkyl”). In certainembodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“C₅₋₆cycloalkyl”). In certain embodiments, a cycloalkyl group has 5 to 10ring carbon atoms (“C₅₋₁₀ cycloalkyl”). Examples of C₅₋₆ cycloalkylgroups include cyclopentyl (C₅) and cyclohexyl (C₅). Examples of C₃₋₆cycloalkyl groups include the aforementioned C₅₋₆ cycloalkyl groups aswell as cyclopropyl (C₃) and cyclobutyl (C₄). Examples of C₃₋₈cycloalkylgroups include the aforementioned C₃₋₆ cycloalkyl groups as well ascycloheptyl (C₇) and cyclooctyl (C₈). In certain embodiments, eachinstance of a cycloalkyl group is independently unsubstituted (an“unsubstituted cycloalkyl”) or substituted (a “substituted cycloalkyl”)with one or more substituents. In certain embodiments, the cycloalkylgroup is unsubstituted C₃₋₁₀ cycloalkyl. In certain embodiments, thecycloalkyl group is substituted C₃₋₁₀ cycloalkyl.

“Heterocyclyl” or “heterocyclic” refers to a radical of a 3- to10-membered non-aromatic ring system having ring carbon atoms and 1 to 4ring heteroatoms, wherein each heteroatom is independently selected fromnitrogen, oxygen, and sulfur (“3-10 membered heterocyclyl”). Inheterocyclyl groups that contain one or more nitrogen atoms, the pointof attachment can be a carbon or nitrogen atom, as valency permits. Aheterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”)or a fused, bridged or spiro-fused ring system such as a bicyclic system(“bicyclic heterocyclyl”), and can be saturated or can be partiallyunsaturated. Heterocyclyl bicyclic ring systems can include one or moreheteroatoms in one or both rings. “Heterocyclyl” also includes ringsystems wherein the heterocyclyl ring, as defined above, is fused withone or more carbocyclyl groups wherein the point of attachment is eitheron the carbocyclyl or heterocyclyl ring, or ring systems wherein theheterocyclyl ring, as defined above, is fused with one or more aryl orheteroaryl groups, wherein the point of attachment is on theheterocyclyl ring, and in such instances, the number of ring memberscontinue to designate the number of ring members in the heterocyclylring system. In certain embodiments, each instance of heterocyclyl isindependently optionally substituted, e.g., unsubstituted (an“unsubstituted heterocyclyl”) or substituted (a “substitutedheterocyclyl”) with one or more substituents. In certain embodiments,the heterocyclyl group is unsubstituted 3-10 membered heterocyclyl. Incertain embodiments, the heterocyclyl group is substituted 3-10 memberedheterocyclyl.

In certain embodiments, a heterocyclyl group is a 5-10 memberednon-aromatic ring system having ring carbon atoms and 1-4 ringheteroatoms, wherein each heteroatom is independently selected fromnitrogen, oxygen, and sulfur (“5-10 membered heterocyclyl”). In certainembodiments, a heterocyclyl group is a 5-8 membered non-aromatic ringsystem having ring carbon atoms and 1-4 ring heteroatoms, wherein eachheteroatom is independently selected from nitrogen, oxygen, and sulfur(“5-8 membered heterocyclyl”). In certain embodiments, a heterocyclylgroup is a 5-6 membered non-aromatic ring system having ring carbonatoms and 1-4 ring heteroatoms, wherein each heteroatom is independentlyselected from nitrogen, oxygen, and sulfur (“5-6 memberedheterocyclyl”). In certain embodiments, the 5-6 membered heterocyclylhas 1-3 ring heteroatoms independently selected from nitrogen, oxygen,and sulfur. In certain embodiments, the 5-6 membered heterocyclyl has1-2 ring heteroatoms independently selected from nitrogen, oxygen, andsulfur. In certain embodiments, the 5-6 membered heterocyclyl has onering heteroatom selected from nitrogen, oxygen, and sulfur.

Exemplary 3-membered heterocyclyl groups containing one heteroatominclude, without limitation, aziridinyl, oxiranyl, and thiiranyl.Exemplary 4-membered heterocyclyl groups containing one heteroatominclude, without limitation, azetidinyl, oxetanyl, and thietanyl.Exemplary 5-membered heterocyclyl groups containing one heteroatominclude, without limitation, tetrahydrofuranyl, dihydrofuranyl,tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl,and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groupscontaining two heteroatoms include, without limitation, dioxolanyl,oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-memberedheterocyclyl groups containing three heteroatoms include, withoutlimitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary6-membered heterocyclyl groups containing one heteroatom include,without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl,and thianyl. Exemplary 6-membered heterocyclyl groups containing twoheteroatoms include, without limitation, piperazinyl, morpholinyl,dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groupscontaining three heteroatoms include, without limitation, triazinanyl.Exemplary 7-membered heterocyclyl groups containing one heteroatominclude, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary8-membered heterocyclyl groups containing one heteroatom include,without limitation, azocanyl, oxecanyl, and thiocanyl. Exemplary5-membered heterocyclyl groups fused to a C₆ aryl ring (also referred toherein as a 5,6-bicyclic heterocyclic ring) include, without limitation,indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl,benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl groupsfused to an aryl ring (also referred to herein as a 6,6-bicyclicheterocyclic ring) include, without limitation, tetrahydroquinolinyl,tetrahydroisoquinolinyl, and the like.

“Aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclicor tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 πelectrons shared in a cyclic array) having 6-14 ring carbon atoms andzero heteroatoms provided in the aromatic ring system (“C₆₋₁₄ aryl”). Incertain embodiments, an aryl group has six ring carbon atoms (“C₆ aryl”;e.g., phenyl). In certain embodiments, an aryl group has ten ring carbonatoms (“C₁₀ aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). Incertain embodiments, an aryl group has fourteen ring carbon atoms (“C₁₄aryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein thearyl ring, as defined above, is fused with one or more carbocyclyl orheterocyclyl groups wherein the radical or point of attachment is on thearyl ring, and in such instances, the number of carbon atoms continue todesignate the number of carbon atoms in the aryl ring system. In certainembodiments, each instance of an aryl group is independently optionallysubstituted, e.g., unsubstituted (an “unsubstituted aryl”) orsubstituted (a “substituted aryl”) with one or more substituents. Incertain embodiments, the aryl group is unsubstituted C₆₋₁₄ aryl. Incertain embodiments, the aryl group is substituted C₆₋₁₄ aryl.

“Heteroaryl” refers to a radical of a 5-10 membered monocyclic orbicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π electronsshared in a cyclic array) having ring carbon atoms and 1-4 ringheteroatoms provided in the aromatic ring system, wherein eachheteroatom is independently selected from nitrogen, oxygen and sulfur(“5-10 membered heteroaryl”). In heteroaryl groups that contain one ormore nitrogen atoms, the point of attachment can be a carbon or nitrogenatom, as valency permits. Heteroaryl bicyclic ring systems can includeone or more heteroatoms in one or both rings. “Heteroaryl” includes ringsystems wherein the heteroaryl ring, as defined above, is fused with oneor more carbocyclyl or heterocyclyl groups wherein the point ofattachment is on the heteroaryl ring, and in such instances, the numberof ring members continue to designate the number of ring members in theheteroaryl ring system. “Heteroaryl” also includes ring systems whereinthe heteroaryl ring, as defined above, is fused with one or more arylgroups wherein the point of attachment is either on the aryl orheteroaryl ring, and in such instances, the number of ring membersdesignates the number of ring members in the fused (aryl/heteroaryl)ring system. Bicyclic heteroaryl groups wherein one ring does notcontain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and thelike) the point of attachment can be on either ring, e.g., either thering bearing a heteroatom (e.g., 2-indolyl) or the ring that does notcontain a heteroatom (e.g., 5-indolyl).

In certain embodiments, a heteroaryl group is a 5-10 membered aromaticring system having ring carbon atoms and 1-4 ring heteroatoms providedin the aromatic ring system, wherein each heteroatom is independentlyselected from nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”).In certain embodiments, a heteroaryl group is a 5-8 membered aromaticring system having ring carbon atoms and 1-4 ring heteroatoms providedin the aromatic ring system, wherein each heteroatom is independentlyselected from nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”).In certain embodiments, a heteroaryl group is a 5-6 membered aromaticring system having ring carbon atoms and 1-4 ring heteroatoms providedin the aromatic ring system, wherein each heteroatom is independentlyselected from nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”).In certain embodiments, the 5-6 membered heteroaryl has 1-3 ringheteroatoms independently selected from nitrogen, oxygen, and sulfur. Incertain embodiments, the 5-6 membered heteroaryl has 1-2 ringheteroatoms independently selected from nitrogen, oxygen, and sulfur. Incertain embodiments, the 5-6 membered heteroaryl has 1 ring heteroatomselected from nitrogen, oxygen, and sulfur. In certain embodiments, eachinstance of a heteroaryl group is independently optionally substituted,e.g., unsubstituted (“unsubstituted heteroaryl”) or substituted(“substituted heteroaryl”) with one or more substituents. In certainembodiments, the heteroaryl group is unsubstituted 5-14 memberedheteroaryl. In certain embodiments, the heteroaryl group is substituted5-14 membered heteroaryl.

Exemplary 5-membered heteroaryl groups containing one heteroatominclude, without limitation, pyrrolyl, furanyl and thiophenyl. Exemplary5-membered heteroaryl groups containing two heteroatoms include, withoutlimitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, andisothiazolyl. Exemplary 5-membered heteroaryl groups containing threeheteroatoms include, without limitation, triazolyl, oxadiazolyl, andthiadiazolyl. Exemplary 5-membered heteroaryl groups containing fourheteroatoms include, without limitation, tetrazolyl. Exemplary6-membered heteroaryl groups containing one heteroatom include, withoutlimitation, pyridinyl. Exemplary 6-membered heteroaryl groups containingtwo heteroatoms include, without limitation, pyridazinyl, pyrimidinyl,and pyrazinyl. Exemplary 6-membered heteroaryl groups containing threeor four heteroatoms include, without limitation, triazinyl andtetrazinyl, respectively. Exemplary 7-membered heteroaryl groupscontaining one heteroatom include, without limitation, azepinyl,oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groupsinclude, without limitation, indolyl, isoindolyl, indazolyl,benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl,benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl,benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl,indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groupsinclude, without limitation, naphthyridinyl, pteridinyl, quinolinyl,isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

“Fused” or “ortho-fused” are used interchangeably herein, and refer totwo rings that have two atoms and one bond in common, e.g.,

“Bridged” refers to a ring system containing (1) a bridgehead atom orgroup of atoms which connect two or more non-adjacent positions of thesame ring; or (2) a bridgehead atom or group of atoms which connect twoor more positions of different rings of a ring system and does notthereby form an ortho-fused ring, e.g.,

“Spiro” or “Spiro-fused” refers to a group of atoms which connect to thesame atom of a carbocyclic or heterocyclic ring system (geminalattachment), thereby forming a ring, e.g.,

Spiro-fusion at a bridgehead atom is also contemplated.

“Partially unsaturated” refers to a group that includes at least onedouble or triple bond. The term “partially unsaturated” is intended toencompass rings having multiple sites of unsaturation, but is notintended to include aromatic groups (e.g., aryl or heteroaryl groups) asherein defined. Likewise, “saturated” refers to a group that does notcontain a double or triple bond, i.e., contains all single bonds.

In certain embodiments, aliphatic, alkyl, alkenyl, alkynyl, carbocyclyl,heterocyclyl, aryl, and heteroaryl groups, as defined herein, areoptionally substituted (e.g., “substituted” or “unsubstituted”aliphatic, “substituted” or “unsubstituted” alkyl, “substituted” or“unsubstituted” alkenyl, “substituted” or “unsubstituted” alkynyl,“substituted” or “unsubstituted” carbocyclyl, “substituted” or“unsubstituted” heterocyclyl, “substituted” or “unsubstituted” aryl or“substituted” or “unsubstituted” heteroaryl group). In general, the term“substituted”, whether preceded by the term “optionally” or not, meansthat at least one hydrogen present on a group (e.g., a carbon ornitrogen atom) is replaced with a permissible substituent, e.g., asubstituent which upon substitution results in a stable compound, e.g.,a compound which does not spontaneously undergo transformation such asby rearrangement, cyclization, elimination, or other reaction. Unlessotherwise indicated, a “substituted” group has a substituent at one ormore substitutable positions of the group, and when more than oneposition in any given structure is substituted, the substituent iseither the same or different at each position. The term “substituted” iscontemplated to include substitution with all permissible substituentsof organic compounds, including any of the substituents described hereinthat results in the formation of a stable compound. The presentdisclosure contemplates any and all such combinations in order to arriveat a stable compound. For purposes of this disclosure, heteroatoms suchas nitrogen may have hydrogen substituents and/or any suitablesubstituent as described herein which satisfy the valencies of theheteroatoms and results in the formation of a stable moiety.

Exemplary carbon atom substituents include, but are not limited to,halogen, —CN, —NO₂, —N₃, —SO₂H, —SO₃H, —OH, —OR^(aa), —ON(R^(bb))₂,—N(R^(bb))₂, —N(R^(bb))₃ ⁺X⁻, —N(OR^(cc))R^(bb), —SH, —SR^(aa),—SSR^(cc), —C(═O)R^(aa), —CO₂H, —CHO, —C(OR^(cc))₂, —CO₂R^(aa),—OC(═O)R^(aa), —OCO₂R^(aa), —C(═O)N(R^(bb))₂, —OC(═O)N(R^(bb))₂,—NR^(bb)C(═O)R^(aa), —NR^(bb)CO₂R^(aa), —NR^(bb)C(═O)N(R^(bb))₂,—C(═NR^(bb))R^(aa), —C(═NR^(bb))OR^(aa), —OC(═NR^(bb))R^(aa),—OC(═NR^(bb))OR^(aa), —C(═NR^(bb))N(R^(bb))₂, —OC(═NR^(bb))N(R^(bb))₂,—NR^(bb)C(═NR^(bb))N(R^(bb))₂, —C(═O)NR^(bb)SO₂R^(aa), NR^(bb)SO₂R^(aa),—SO₂N(R^(bb))₂, —SO₂R^(aa), —SO₂OR^(aa), —OSO₂R^(aa), —S(═O)R^(aa),—OS(═O)R^(aa), —Si(R^(aa))₃, —OSi(R^(aa))₃—C(═S)N(R^(bb))₂,—C(═O)SR^(aa), —C(═S)SR^(aa), —SC(═S)SR^(aa), —SC(═O)SR^(aa),—OC(═O)SR^(aa), —SC(═O)OR^(aa), —SC(═O)R^(aa), —P(═O)₂R^(aa),—OP(═O)₂R^(aa), —P(═O)(R^(aa))₂, —OP(═O)(R^(aa))₂, —OP(═O)(OR^(cc))₂,—P(═O)₂N(R^(bb))₂, —OP(═O)₂N(R^(bb))₂, —P(═O)(NR^(bb))₂,—OP(═O)(NR^(bb))₂, —NR^(bb)P(═O)(OR^(cc))₂, —NR^(bb)P(═O)(NR^(bb))₂,—P(R^(cc))₂, —P(R^(cc))₃, —OP(R^(cc))₂, —OP(R^(cc))₃, —B(R^(aa))₂,—B(OR^(cc))₂, —BR^(aa)(OR^(cc)), C₁₋₁₀ alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ carbocyclyl, 3-14 membered heterocyclyl,C₆₋₁₄ aryl, and 5-14 membered heteroaryl, wherein each alkyl, alkenyl,alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl isindependently substituted with 0, 1, 2, 3, 4, or 5 R^(dd) groups;

or two geminal hydrogens on a carbon atom are replaced with the group═O, ═S, ═NN(R^(bb))₂, ═NNR^(bb)C(═O)R^(aa), ═NNR^(bb)C(═O)OR^(aa),═NNR^(bb)S(═O)₂R^(aa), ═NR^(bb), or ═NOR^(cc);

each instance of R^(aa) is, independently, selected from C₁₋₁₀ alkyl,C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ carbocyclyl,3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 membered heteroaryl, ortwo R^(aa) groups are joined to form a 3-14 membered heterocyclyl or5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl,carbocyclyl, heterocyclyl, aryl, and heteroaryl is independentlysubstituted with 0, 1, 2, 3, 4, or 5 R^(dd) groups;

each instance of R^(bb) is, independently, selected from hydrogen, —OH,—OR^(aa), —N(R^(cc))₂, —CN, —C(═O)R^(aa), —C(═O)N(R^(cc))₂, —CO₂R^(aa),—SO₂R^(aa), —C(═NR^(cc))OR^(aa), —C(═NR^(cc))N(R^(cc))₂, —SO₂N(R^(cc))₂,—SO₂R^(cc), —SO₂OR^(cc), —SOR^(aa), —C(═S)N(R^(cc))₂, —C(═O)SR^(cc),—C(═S)SR^(cc), —P(═O)₂R^(aa), —P(═O)(R^(aa))₂, —P(═O)₂N(R^(cc))₂,—P(═O)(NR^(cc))₂, C₁₋₁₀ alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀alkynyl, C₃₋₁₀ carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and5-14 membered heteroaryl, or two R^(bb) groups are joined to form a 3-14membered heterocyclyl or 5-14 membered heteroaryl ring, wherein eachalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroarylis independently substituted with 0, 1, 2, 3, 4, or 5 R^(dd) groups;

each instance of R^(cc) is, independently, selected from hydrogen,C₁₋₁₀alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 memberedheteroaryl, or two R^(cc) groups are joined to form a 3-14 memberedheterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl,alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl isindependently substituted with 0, 1, 2, 3, 4, or 5 R^(dd) groups;

each instance of R^(dd) is, independently, selected from halogen, —CN,—NO₂, —N₃, —SO₂H, —SO₃H, —OH, —OR^(ee), —ON(R^(ff))₂, —N(R^(ff))₂,—N(R^(ff))₃ ⁺X⁻, —N(OR^(ee))R^(ff), —SH, —SR^(ee), —SSR^(ee),—C(═O)R^(ee), —CO₂H, —CO₂R^(ee), —OC(═O)R^(ee), —OCO₂R^(ee),—C(═O)N(R^(ff))₂, —OC(═O)N(R^(ff))₂, —NR^(ff)C(═O)R^(ee),—NR^(ff)CO₂R^(ee), —NR^(ff)C(═O)N(R^(ff))₂, —C(═NR^(ff))OR^(ee),OC(═NR^(ff))R^(ee), —OC(═NR^(ff))OR^(ee), —C(═NR)N(R^(ff))₂,—OC(═NR^(ff))N(R^(ff))₂, —NR^(ff)C(═NR^(ff))N(R^(ff))₂,—NR^(ff)SO₂R^(ee), —SO₂N(R^(ff))₂, —SO₂R^(ee), —SO₂OR^(ee), —OSO₂R^(ee),—S(═O)R^(ee), —Si(R^(ee))₃, —OSi(R^(ee))₃, —C(═S)N(R^(ff))₂,—C(═O)SR^(ee), —C(═S)SR^(ee), —SC(═S)SR^(ee), —P(═O)₂R^(ee),—P(═O)(R^(ee))₂, —OP(═O)(R^(ee))₂, —OP(═O)(OR^(ee))₂, C₁₋₆ alkyl, C₁₋₆perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ carbocyclyl, 3-10membered heterocyclyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, whereineach alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, andheteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^(gg)groups, or two geminal R^(dd) substituents can be joined to form ═O or═S;

each instance of R^(ee) is, independently, selected from C₁₋₆ alkyl,C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ carbocyclyl, C₆₋₁₀aryl, 3-10 membered heterocyclyl, and 3-10 membered heteroaryl, whereineach alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, andheteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^(gg)groups;

each instance of R^(ff) is, independently, selected from hydrogen, C₁₋₆alkyl, C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ carbocyclyl,3-10 membered heterocyclyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl, ortwo R^(ff) groups are joined to form a 3-14 membered heterocyclyl or5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl,carbocyclyl, heterocyclyl, aryl, and heteroaryl is independentlysubstituted with 0, 1, 2, 3, 4, or 5 R^(gg) groups; and

each instance of R^(gg) is, independently, halogen, —CN, —NO₂, —N₃,—SO₂H, —SO₃H, —OH, —OC₁₋₆ alkyl, —ON(C₁₋₆ alkyl)₂, —N(C₁₋₆ alkyl)₂,—N(C₁₋₆ alkyl)₃ ⁺X⁻, —NH(C₁₋₆ alkyl)₂ ⁺X⁻, —NH₂(C₁₋₆ alkyl)⁺X⁻, —NH₃⁺X⁻, —N(OC₁₋₆ alkyl)(C₁₋₆ alkyl), —N(OH)(C₁₋₆ alkyl), —NH(OH), —SH,—SC₁₋₆ alkyl, —SS(C₁₋₆ alkyl), —C(═O)(C₁₋₆ alkyl), —CO₂H, —CO₂(C₁₋₆alkyl), —OC(═O)(C₁₋₆ alkyl), —OCO₂(C₁₋₆ alkyl), —C(═O)NH₂, —C(═O)N(C₁₋₆alkyl)₂, —OC(═O)NH(C₁₋₆ alkyl), —NHC(═O)(C₁₋₆ alkyl), —N(C₁₋₆alkyl)C(═O)(C₁₋₆ alkyl), —NHCO₂(C₁₋₆ alkyl), —NHC(═O)N(C₁₋₆alkyl)₂,—NHC(═O)NH(C₁₋₆alkyl), —NHC(═O)NH₂, —C(═NH)O(C₁₋₆ alkyl),—OC(═NH)(C₁₋₆alkyl), —OC(═NH)OC₁₋₆alkyl, —C(═NH)N(C₁₋₆ alkyl)₂,—C(═NH)NH(C₁₋₆alkyl), —C(═NH)NH₂, —OC(═NH)N(C₁₋₆ alkyl)₂, —OC(NH)NH(C₁₋₆alkyl), —OC(NH)NH₂, —NHC(NH)N(C₁₋₆ alkyl)₂, —NHC(═NH)NH₂, —NHSO₂(C₁₋₆alkyl), —SO₂N(C₁₋₆ alkyl)₂, —SO₂NH(C₁₋₆ alkyl), —SO₂NH₂, —SO₂C₁₋₆ alkyl,—SO₂OC₁₋₆ alkyl, —OSO₂C₁₋₆alkyl, —SOC₁₋₆ alkyl, —Si(C₁₋₆ alkyl)₃,—OSi(C₁₋₆ alkyl)₃-C(═S)N(C₁₋₆ alkyl)₂, C(═S)NH(C₁₋₆ alkyl), C(═S)NH₂,—C(═O)S(C₁₋₆ alkyl), —C(═S)SC₁₋₆ alkyl, —SC(═S)SC₁₋₆ alkyl,—P(═O)₂(C₁₋₆alkyl), —P(═O)(C₁₋₆ alkyl)₂, —OP(═O)(C₁₋₆ alkyl)₂,—OP(═O)(OC₁₋₆ alkyl)₂, C₁₋₆ alkyl, C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ carbocyclyl, C₆₋₁₀ aryl, 3-10 membered heterocyclyl, 5-10membered heteroaryl; or two geminal R^(gg) substituents can be joined toform ═O or ═S; wherein X is a counterion.

A “counterion” or “anionic counterion” is a negatively charged groupassociated with a cationic quaternary amino group in order to maintainelectronic neutrality. Exemplary counterions include halide ions (e.g.,F⁻, Cl⁻, Br⁻, I⁻), NO₃ ⁻, ClO₄ ⁻, OH⁻, H₂PO₄ ⁻, HSO₄ ⁻, sulfonate ions(e.g., methansulfonate, trifluoromethanesulfonate, p-toluenesulfonate,benzenesulfonate, 10-camphor sulfonate, naphthalene-2-sulfonate,naphthalene-1-sulfonic acid-5-sulfonate, ethan-1-sulfonicacid-2-sulfonate, and the like), and carboxylate ions (e.g., acetate,ethanoate, propanoate, benzoate, glycerate, lactate, tartrate,glycolate, and the like).

“Halo” or “halogen” refers to fluorine (fluoro, —F), chlorine (chloro,—Cl), bromine (bromo, —Br), or iodine (iodo, —I).

Nitrogen atoms can be substituted or unsubstituted as valency permits,and include primary, secondary, tertiary, and quarternary nitrogenatoms. Exemplary nitrogen atom substitutents include, but are notlimited to, hydrogen, —OH, —OR^(aa), —N(R^(cc))₂, —CN, —C(═O)R^(aa),—C(═O)N(R^(cc))₂, —CO₂R, —SO₂R^(aa), —C(═NR^(bb))R^(aa),—C(═NR^(cc))OR^(aa), —C(═NR^(cc))N(R^(cc))₂, —SO₂N(R^(cc))₂, —SO₂R^(cc),—SO₂OR^(cc), —SOR^(aa), —C(═S)N(R^(cc))₂, —C(═O)SR^(cc), —C(═S)SR^(cc),—P(═O)₂R^(aa), —P(═O)(R^(aa))₂, —P(═O)₂N(R^(cc))₂, —P(═O)(NR^(cc))₂,C₁₋₁₀ alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 memberedheteroaryl, or two R^(cc) groups attached to a nitrogen atom are joinedto form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring,wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl,and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5R^(dd) groups, and wherein R^(aa), R^(bb), R^(cc) and R^(dd) are asdefined above.

In certain embodiments, the substituent present on a nitrogen atom is anitrogen protecting group (also referred to as an amino protectinggroup). Nitrogen protecting groups include, but are not limited to, —OH,—OR, —N(R^(cc))₂, —C(═O)R^(aa), —C(═O)N(R^(cc))₂, —CO₂R^(aa),—SO₂R^(aa), —C(═NR^(cc))R^(aa), —C(═NR^(cc))OR^(aa),—C(═NR^(cc))N(R^(cc))₂, —SO₂N(R^(cc))₂, —SO₂R^(cc), —SO₂OR^(cc),—SOR^(aa), —C(═S)N(R^(cc))₂, —C(═O)SR^(cc), —C(═S)SR^(cc), C₁₋₁₀ alkyl(e.g., aralkyl, heteroaralkyl), C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 memberedheteroaryl groups, wherein each alkyl, alkenyl, alkynyl, carbocyclyl,heterocyclyl, aralkyl, aryl, and heteroaryl is independently substitutedwith 0, 1, 2, 3, 4, or 5 R^(dd) groups, and wherein R^(aa), R^(bb),R^(cc), and R^(dd) are as defined herein. Nitrogen protecting groups arewell known in the art and include those described in detail inProtecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts,3^(rd) edition, John Wiley & Sons, 1999, incorporated herein byreference.

Amide nitrogen protecting groups (e.g., —C(═O)R^(aa)) include, but arenot limited to, formamide, acetamide, chloroacetamide,trichloroacetamide, trifluoroacetamide, phenylacetamide,3-phenylpropanamide, picolinamide, 3-pyridylcarboxamide,N-benzoylphenylalanyl derivative, benzamide, p-phenylbenzamide,o-nitophenylacetamide, o-nitrophenoxyacetamide, acetoacetamide,(N′-dithiobenzyloxyacylamino)acetamide, 3-(p-hydroxyphenyl)propanamide,3-(o-nitrophenyl)propanamide, 2-methyl-2-(o-nitrophenoxy)propanamide,2-methyl-2-(o-phenylazophenoxy)propanamide, 4-chlorobutanamide,3-methyl-3-nitrobutanamide, o-nitrocinnamide, N-acetylmethionine,o-nitrobenzamide, and o-(benzoyloxymethyl)benzamide.

Carbamate nitrogen protecting groups (e.g., —C(═O)OR^(aa)) include, butare not limited to, methyl carbamate, ethyl carbamante,9-fluorenylmethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethylcarbamate, 9-(2,7-dibromo)fluoroenylmethyl carbamate,2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methylcarbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc),2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate(Teoc), 2-phenylethyl carbamate (hZ), 1-(1-adamantyl)-1-methylethylcarbamate (Adpoc), 1,1-dimethyl-2-haloethyl carbamate,1,1-dimethyl-2,2-dibromoethyl carbamate (DB-t-BOC),1,1-dimethyl-2,2,2-trichloroethyl carbamate (TCBOC),1-methyl-1-(4-biphenylyl)ethyl carbamate (Bpoc),1-(3,5-di-t-butylphenyl)-1-methylethyl carbamate (t-Bumeoc), 2-(2′- and4′-pyridyl)ethyl carbamate (Pyoc), 2-(N,N-dicyclohexylcarboxamido)ethylcarbamate, t-butyl carbamate (BOC), 1-adamantyl carbamate (Adoc), vinylcarbamate (Voc), allyl carbamate (Alloc), 1-isopropylallyl carbamate(Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc),8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyldithiocarbamate, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz),p-nitobenzyl carbamate, p-bromobenzyl carbamate, p-chlorobenzylcarbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzylcarbamate (Msz), 9-anthrylmethyl carbamate, diphenylmethyl carbamate,2-methylthioethyl carbamate, 2-methylsulfonylethyl carbamate,2-(p-toluenesulfonyl)ethyl carbamate, [2-(1,3-dithianyl)]methylcarbamate (Dmoc), 4-methylthiophenyl carbamate (Mtpc),2,4-dimethylthiophenyl carbamate (Bmpc), 2-phosphonioethyl carbamate(Peoc), 2-triphenylphosphonioisopropyl carbamate (Ppoc),1,1-dimethyl-2-cyanoethyl carbamate, m-chloro-p-acyloxybenzyl carbamate,p-(dihydroxyboryl)benzyl carbamate, 5-benzisoxazolylmethyl carbamate,2-(trifluoromethyl)-6-chromonylmethyl carbamate (Tcroc), m-nitrophenylcarbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate,3,4-dimethoxy-6-nitrobenzyl carbamate, phenyl(o-nitrophenyl)methylcarbamate, t-amyl carbamate, S-benzyl thiocarbamate, p-cyanobenzylcarbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentylcarbamate, cyclopropylmethyl carbamate, p-decyloxybenzyl carbamate,2,2-dimethoxyacylvinyl carbamate, o-(N,N-dimethylcarboxamido)benzylcarbamate, 1,1-dimethyl-3-(N,N-dimethylcarboxamido)propyl carbamate,1,1-dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate,2-furanylmethyl carbamate, 2-iodoethyl carbamate, isoborynl carbamate,isobutyl carbamate, isonicotinyl carbamate,p-(p′-methoxyphenylazo)benzyl carbamate, 1-methylcyclobutyl carbamate,1-methylcyclohexyl carbamate, 1-methyl-1-cyclopropylmethyl carbamate,1-methyl-1-(3,5-dimethoxyphenyl)ethyl carbamate,1-methyl-1-(p-phenylazophenyl)ethyl carbamate, 1-methyl-1-phenylethylcarbamate, 1-methyl-1-(4-pyridyl)ethyl carbamate, phenyl carbamate,p-(phenylazo)benzyl carbamate, 2,4,6-tri-t-butylphenyl carbamate,4-(trimethylammonium)benzyl carbamate, and 2,4,6-trimethylbenzylcarbamate.

Sulfonamide nitrogen protecting groups (e.g., —S(═O)₂R^(aa)) include,but are not limited to, p-toluenesulfonamide (Ts), benzenesulfonamide,2,3,6, -trimethyl-4-methoxybenzenesulfonamide (Mtr),2,4,6-trimethoxybenzenesulfonamide (Mtb),2,6-dimethyl-4-methoxybenzenesulfonamide (Pme),2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte),4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide(Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds),2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide(Ms), β-trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide,4-(4′,8′-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS),benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide.

Other nitrogen protecting groups include, but are not limited to,phenothiazinyl-(10)-acyl derivative, N′-p-toluenesulfonylaminoacylderivative, N′-phenylaminothioacyl derivative, N-benzoylphenylalanylderivative, N-acetylmethionine derivative,4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts),N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole,N-1,1,4,4-tetramethyldisilylazacyclopentane adduct (STABASE),5-substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one, 5-substituted1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, 1-substituted3,5-dinitro-4-pyridone, N-methylamine, N-allylamine,N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine,N-(1-isopropyl-4-nitro-2-oxo-3-pyroolin-3-yl)amine, quaternary ammoniumsalts, N-benzylamine, N-di(4-methoxyphenyl)methylamine,N-5-dibenzosuberylamine, N-triphenylmethylamine (Tr),N-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr),N-9-phenylfluorenylamine (PhF),N-2,7-dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino (Fcm),N-2-picolylamino N′-oxide, N-1,1-dimethylthiomethyleneamine,N-benzylideneamine, N-p-methoxybenzylideneamine,N-diphenylmethyleneamine, N-[(2-pyridyl)mesityl]methyleneamine,N—(N′,N′-dimethylaminomethylene)amine, N,N′-isopropylidenediamine,N-p-nitrobenzylideneamine, N-salicylideneamine,N-5-chlorosalicylideneamine,N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine,N-cyclohexylideneamine, N-(5,5-dimethyl-3-oxo-1-cyclohexenyl)amine,N-borane derivative, N-diphenylborinic acid derivative,N-[phenyl(pentaacylchromium- or tungsten)acyl]amine, N-copper chelate,N-zinc chelate, N-nitroamine, N-nitrosoamine, amine N-oxide,diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt),diphenylthiophosphinamide (Ppt), dialkyl phosphoramidates, dibenzylphosphoramidate, diphenyl phosphoramidate, benzenesulfenamide,o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide,pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide,triphenylmethylsulfenamide, and 3-nitropyridinesulfenamide (Npys).

In certain embodiments, the substituent present on an oxygen atom is anoxygen protecting group (also referred to as a hydroxyl protectinggroup). Oxygen protecting groups include, but are not limited to,—R^(aa), —N(R^(bb))₂, —C(═O)SR^(aa), —C(═O)R^(aa), —CO₂R^(aa),—C(═O)N(R^(bb))₂, —C(═NR^(bb))R^(aa), —C(═NR^(bb))OR^(aa),—C(═NR^(bb))N(R^(bb))₂, —S(═O)R^(aa), —SO₂R^(aa), —Si(R^(aa))₃,—P(R^(cc))₂, —P(R^(cc))₃, —P(═O)₂R^(aa), —P(═O)(R^(aa))₂,—P(═O)(OR^(cc))₂, —P(═O)₂N(R^(bb))₂, and —P(═O)(NR^(bb))₂, whereinR^(aa), R^(bb), and R^(cc) are as defined herein. Oxygen protectinggroups are well known in the art and include those described in detailin Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M.Wuts, 3^(rd) edition, John Wiley & Sons, 1999, incorporated herein byreference.

Exemplary oxygen protecting groups include, but are not limited to,methyl, methoxylmethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl,(phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM),p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM),guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM),siloxymethyl, 2-methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl,bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl (SEMOR),tetrahydropyranyl (THP), 3-bromotetrahydropyranyl,tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl(MTHP), 4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranylS,S-dioxide, 1-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl(CTMP), 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl,2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl,1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl,1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl,2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl,t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl,benzyl (Bn), p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl,p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl,p-phenylbenzyl, 2-picolyl, 4-picolyl, 3-methyl-2-picolyl N-oxido,diphenylmethyl, p,p′-dinitrobenzhydryl, 5-dibenzosuberyl,triphenylmethyl, α-naphthyldiphenylmethyl,p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl,tri(p-methoxyphenyl)methyl, 4-(4′-bromophenacyloxyphenyl)diphenylmethyl,4,4′,4″-tris(4,5-dichlorophthalimidophenyl)methyl,4,4′,4″-tris(levulinoyloxyphenyl)methyl,4,4′,4″-tris(benzoyloxyphenyl)methyl,3-(imidazol-1-yl)bis(4′,4″-dimethoxyphenyl)methyl,1,1-bis(4-methoxyphenyl)-1′-pyrenylmethyl, 9-anthryl,9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl,1,3-benzodisulfuran-2-yl, benzisothiazolyl S,S-dioxido, trimethylsilyl(TMS), triethylsilyl (TES), triisopropylsilyl (TIPS),dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS),dimethylthexylsilyl, t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl(TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl,diphenylmethylsilyl (DPMS), t-butylmethoxyphenylsilyl (TBMPS), formate,benzoylformate, acetate, chloroacetate, dichloroacetate,trichloroacetate, trifluoroacetate, methoxyacetate,triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate,3-phenylpropionate, 4-oxopentanoate (levulinate),4,4-(ethylenedithio)pentanoate (levulinoyldithioacetal), pivaloate,adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate,2,4,6-trimethylbenzoate (mesitoate), alkyl methyl carbonate,9-fluorenylmethyl carbonate (Fmoc), alkyl ethyl carbonate, alkyl2,2,2-trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate(TMSEC), 2-(phenylsulfonyl) ethyl carbonate (Psec),2-(triphenylphosphonio) ethyl carbonate (Peoc), alkyl isobutylcarbonate, alkyl vinyl carbonate alkyl allyl carbonate, alkylp-nitrophenyl carbonate, alkyl benzyl carbonate, alkyl p-methoxybenzylcarbonate, alkyl 3,4-dimethoxybenzyl carbonate, alkyl o-nitrobenzylcarbonate, alkyl p-nitrobenzyl carbonate, alkyl S-benzyl thiocarbonate,4-ethoxy-1-napththyl carbonate, methyl dithiocarbonate, 2-iodobenzoate,4-azidobutyrate, 4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate,2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl,4-(methylthiomethoxy)butyrate, 2-(methylthiomethoxymethyl)benzoate,2,6-dichloro-4-methylphenoxyacetate,2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate,2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate,isobutyrate, monosuccinoate, (E)-2-methyl-2-butenoate,o-(methoxyacyl)benzoate, α-naphthoate, nitrate, alkylN,N,N′,N′-tetramethylphosphorodiamidate, alkyl N-phenylcarbamate,borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate,sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate(Ts).

In certain embodiments, the substituent present on a sulfur atom is asulfur protecting group (also referred to as a thiol protecting group).Sulfur protecting groups include, but are not limited to, —R^(aa),—N(R^(bb))₂, —C(═O)SR^(aa), —C(═O)R^(aa), —CO₂R^(aa), —C(═O)N(R^(bb))₂,—C(═NR^(bb))R^(aa), —C(═NR^(bb))OR^(aa), —C(═NR^(bb))N(R^(bb))₂,—S(═O)R^(aa), —SO₂R^(aa), —Si(R^(aa))₃, —P(R^(cc))₂, —P(R^(cc))₃,—P(═O)₂R, —P(═O)(R^(aa))₂, —P(═O)(OR^(cc))₂, —P(═O)₂N(R^(bb))₂, and—P(═O)(NR^(bb))₂, wherein R^(aa), R^(bb), and R^(cc) are as definedherein. Sulfur protecting groups are well known in the art and includethose described in detail in Protecting Groups in Organic Synthesis, T.W. Greene and P. G. M. Wuts, 3rd edition, John Wiley & Sons, 1999,incorporated herein by reference.

These and other exemplary substituents are described in more detail inthe Detailed Description, Examples, and claims. The present disclosureis not intended to be limited in any manner by the above exemplarylisting of substituents.

The term “acyl,” used alone or a part of a larger moiety, refers togroups formed by removing a hydroxy group from a carboxylic acid.Exemplary acyl groups include, without limitation, —C(═O)Me, —C(═O)Et,—C(═O)i-Pr, —C(═O)aryl, and —C(═O)CH₂F.

The term “Lewis acid” refers to a species as defined by IUPAC, that is“a molecular entity (and the corresponding chemical species) that is anelectron-pair acceptor and therefore able to react with a Lewis base toform a Lewis adduct, by sharing the electron pair furnished by the Lewisbase.” Exemplary Lewis acids include, without limitation, borontrifluoride, aluminum trichloride, tin tetrachloride, titaniumtetrachloride, and iron tribromide.

The term “Brønsted acid” refers to a protic or proton-donating species.Exemplary Brønsted acids include, without limitation, acetic acid,triflic acid, hydrochloric acid, and barbituric acid.

The term “acid anhydride” refers to an organic compound that has twoacyl, phosphoryl, or sulfonyl groups bound to the same oxygen atom. Mostcommonly, the acyl groups are derived from the same carboxylic acid. Oneor both acyl groups of an acid anhydride may also be derived fromanother type of organic acid, such as sulfonic acid or a phosphonicacid. One of the acyl groups of an acid anhydride can be derived from aninorganic acid such as phosphoric acid. Exemplary acid anhydridesinclude, without limitation, acetic anhydride, maleic anhydride, andtriflic anhydride.

The term “PhenoFluor” refers to the trade name for the fluorinatingreagent1,3-bis(2,6-diisopropylphenyl)-2,2-difluoro-2,3-dihydro-1H-imidazole.The invention is described in international application,PCT/US2012/033125, published as WO 12/142162, which is incorporatedherein by reference.

The term “no-carrier-added” or “non-carrier-added” reaction typicallyrefers to a reaction carried out with preparation of a radioactiveisotope without deliberate addition of a non-radioactive isotope.However, in the context of the preparation of PET imaging agents labeledwith ¹⁸F, using only the radioactive isotope would be ideal but can bepractically challenging or even impossible due to the very lowquantities of the ¹⁸F-labelled reagent (e.g., K¹⁸F) relative to theorganic reactant. Inefficient reactions will therefore rely on theinclusion of excess “carrier” stable isotope (e.g., ¹⁹F) in order topromote reaction progress, thus producing PET imaging agents of lowerradioactivity. Therefore, development of “non-carrier-added” reactionsis beneficial for the generation of high-specific activity agents, butsometimes this cannot be achieved based on a given reaction and/orsubstrate.

The term “solid support” refers a material to which a compound isattached to facilitate identification, isolation, purification, orchemical reaction selectivity of the compound. Such materials are knownin the art and include, for example, beads, pellets, disks, fibers,gels, or particles such as cellulose beads, pore-glass beads, silicagels, polystyrene beads optionally cross-linked with divinylbenzene andoptionally grafted with polyethylene glycol, poly-acrylamide beads,latex beads, dimethylacrylamide beads optionally cross-linked withN,N′-bis-acryloyl ethylene diamine, glass particles coated withhydrophobic polymer, and material having a rigid or semi-rigid surface.The solid supports optionally have functional groups such as amino,hydroxy, carboxy, or halo groups, (see, Obrecht, D. and Villalgrodo, J.M., Solid-Supported Combinatorial and Parallel Synthesis ofSmall-Molecular-Weight Compound Libraries, Pergamon-Elsevier ScienceLimited (1998)), and include those useful in techniques such as the“split and pool” or “parallel” synthesis techniques, solid-phase andsolution-phase techniques, and encoding techniques (see, for example,Czarnik, A. W., Curr. Opin. Chem. Bio., (1997) 1, 60).

The term “stereospecific” refers to the property of a reaction mechanismthat leads to different stereoisomeric reaction products from differentstereoisomeric reactants, or which operates on only one (or a subset) ofthe stereoisomers. An example of a stereospecific reaction includes, butis not limited to, a nucleophilic substitution reaction (S_(n) ²) at ansp³ stereocenter, leading to perfect inversion of stereochemistrywithout erosion of enantiomeric purity.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS OF THE INVENTION

As described above, functionalized aryl fluorides find frequent use aspharmaceuticals and agrochemicals, in part due to their favorablepharmacological properties such as increased metabolic stability.Besides the vast number of applications of fluorinated organic moleculesbearing the natural ¹⁹F isotope, compounds bearing the radioisotope ¹⁸Fare invaluable as ligands for Positron Emission Tomography (PET). Thelow reactivity of ¹⁸F⁻ towards arenes renders radiofluorinationchallenging particularly for complex substrates that require mildreaction conditions. The potential biomedical applications of PET forstudying a variety of diseases such as cancer, cardiovascular disease,autoimmunity, neurodegeneration, and psychiatric illness are impeded bythe lack of suitable ¹⁸F-based PET tracers. Various synthetic methodsused to make PET tracers (e.g., nucleophilic substitution chemistry,incorporation into diaryl iodonium salts) are not broadly applicable.

The inventors have previously described a reagent for fluorination (seeFIG. 2). The reagent, known as PhenoFluor®, exhibits exceptionalsubstrate scope and functional group tolerance. The new reagents ofFormula (I) provide access to late-stage fluorination similar toPhenoFluor®, but without the need for additional fluoride, so thatno-carrier-added (nca) reactions become feasible.

The new fluorinating reagent is capable of site-specific substitution ofhydroxyl groups with non-carrier-added ¹⁸F-fluoride in a one-steptransformation. The transformation is metal-free and combines thesubstrate scope of late-stage fluorination with the convenient andbroadly implemented reaction set-up of simple displacement chemistry.The use of readily available phenols or alcohols as labeling precursorsallows rapid access to new PET probes. Development of this method ofradiofluorination into a fully automated, versatile ¹⁸F-labelingprotocol will considerably streamline tracer development through thesynthesis of desirable PET probes.

Described herein are methods of fluorinating reagents and methods ofmaking fluorinated organic compounds. Upon making a fluorinating reagent(which may be isolated or used in situ) a reaction of a hydroxylgroup-containing organic compound or tautomer thereof and a fluorinatingagent is described herein. This subsequent reaction provides afluorinated organic compound in which the hydroxyl group (or tautomericcarbonyl) of the organic compound is replaced with a fluorinesubstituent (for example, FIG. 1).

The reaction is not limited to phenyl and aliphatic and may contain anumber of other chemical groups. Typical groups include, withoutlimitation, alkyl (e.g., C₁, C₂, C₃, C₄, C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁,C₁₂ straight or branched chain alkyl), cycloalkyl, haloalkyl (e.g.,perfluoroalkyl such as CF₃), aryl, heteroaryl, aralkyl, heteroaralkyl,heterocyclyl, alkenyl, alkynyl, cycloalkenyl, heterocycloalkenyl,alkoxy, haloalkoxy (e.g., perfluoroalkoxy such as OCF₃), halo, hydroxy,carboxy, carboxylate, cyano, nitro, amino, alkylamino, dialkylamino,SO₃H, sulfate, phosphate, methylenedioxy (—O—CH₂—O— wherein oxygens areattached to vicinal atoms), ethylenedioxy, oxo, thioxo (e.g., C═S),imino (alkyl, aryl, aralkyl), S(O)_(n)alkyl (where n is 0-2), S(O)_(n)aryl (where n is 0-2), S(O)_(n) heteroaryl (where n is 0-2), S(O)_(n)heterocyclyl (where n is 0-2), amine (mono-, di-, alkyl, cycloalkyl,aralkyl, heteroaralkyl, aryl, heteroaryl, and combinations thereof),ester (alkyl, aralkyl, heteroaralkyl, aryl, heteroaryl), amide (mono-,di-, alkyl, aralkyl, heteroaralkyl, aryl, heteroaryl, and combinationsthereof), sulfonamide (mono-, di-, alkyl, aralkyl, heteroaralkyl, andcombinations thereof). The substituents are independently any onesingle, or any subset of the aforementioned substituents. A substituentmay itself be substituted with any one of the above substituents. Incertain embodiments, two groups may be taken together to form a ring,e.g., an aryl, heteroaryl, cyclyl or heterocyclyl ring, which may itselfbe further substituted with any one of the above substituents.

In one aspect, the present invention is directed to a compound ofFormula (I):

wherein

D is oxygen or sulfur;

A is hydrogen or a Lewis acid;

Q is an anion;

R¹ and R² are independently selected from the group consisting of C₁₋₆alkyl, C₆₋₁₀ aryl, C₆₋₁₀ aralkyl, 5-10 membered heteroaryl, 5-10membered heteroaralkyl, 4-10 membered heterocyclyl, 4-10 memberedheterocyclylalkyl, 3-10 membered carbocyclyl, and 3-10 memberedcarbocyclylalkyl, each of which is optionally substituted with 0 to 5occurrences of R⁵;

R³ and R⁴ are independently selected from the group consisting ofhydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, nitro, cyano, halo,C₁₋₆ haloalkyl, C₁₋₆ alkoxy, optionally substituted C₆₋₁₀ aryl,optionally substituted C₆₋₁₀ aralkyl, optionally substituted 5-10membered heteroaryl, optionally substituted 4-10 membered heterocyclyl,optionally substituted 3-10 membered carbocyclyl, optionally substituted4-10 membered heterocyclylalkyl, acyl, —NH₂, —NHR⁷, —N(R⁷)₂, —OH, —SH,—SO₂R⁷, —SOR⁷, —SO₂NR⁷ ₂, and —SR⁷;

R⁷ is independently selected from the group consisting of hydrogen,acyl, optionally substituted aliphatic, optionally substitutedcarbocyclyl, optionally substituted heterocyclyl, optionally substitutedaryl, and optionally substituted heteroaryl, or two R⁷ groups are takentogether with their intervening atoms to form an optionally substitutedheterocyclic ring;

R⁵ is independently selected from the group consisting of halo, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy,optionally substituted C₆₋₁₀ aryl, optionally substituted 5-10 memberedheteroaryl, optionally substituted 4-10 membered heterocyclyl,optionally substituted 3-10 membered carbocyclyl, nitro, cyano, acyl,—NH₂, —NHR⁷, —N(R⁷)₂, —OH, —SH, —SO₂R⁷, —SOR⁷, —SO₂NR⁷ ₂, and —SR⁷;

t is the anion charge number, ranging from 1-3;

v is 0-3; and

m is 1-5.

In certain embodiments, the compound of Formula (I) is a compound ofFormula (I-a):

In certain embodiments, the compound of Formula (I) is a compound ofFormula (I-b):

In certain embodiments, D is oxygen. In certain embodiments, D issulfur.

In certain embodiments, A is hydrogen, m is 1, and v is 1. In certainembodiments, A is hydrogen, m is 1, v is 1, and t is 1. In certainembodiments, A is a Lewis acid, m is 1-4, and v is 0 or 1. In certainembodiments, A is a Lewis acid, m is 1, and v is 0. In certainembodiments, A is a Lewis acid, m is 1, and v is 1. In certainembodiments, A is a Lewis acid, m is 2, and v is 0. In certainembodiments, A is a Lewis acid, m is 2, and v is 1. In certainembodiments, A is a Lewis acid, m is 3, and v is 0. In certainembodiments, A is a Lewis acid, m is 3, and v is 1. In certainembodiments, A is a Lewis acid, m is 4, and v is 0. In certainembodiments, A is a Lewis acid, m is 4, and v is 1.

In certain embodiments, t is 1. In certain embodiments, t is 2. Incertain embodiments, t is 3.

In certain embodiments, the compound of Formula (I) is a compound ofFormula (I-c):

In certain embodiments, the compound of Formula (I) is a compound ofFormula (I-d):

In certain embodiments, Q of Formula (I) is any suitable counterion. Incertain embodiments, Q of Formula (I) is halogen (e.g., fluoro, chloro,bromo, or iodo), trifluoroacetate, trichloroacetate, NO₂ ⁻, NO₃ ⁻, H₂PO₄⁻, PF₆ ⁻, HF²⁻, HSO₄ ⁻, SbF₆ ⁻, ClO₄ ⁻, SO₄ ⁻², (R⁶)SO₃ ⁻, OTf⁻, OTs⁻,ONf⁻, ONs⁻, BF₄ ⁻, or B(R⁶)₄ ⁻, wherein R⁶ is C₁₋₆ alkyl, —OR⁷, C₆₋₁₀aryl, C₆₋₁₀ aralkyl, 5-10 membered heteroaryl, 5-10 memberedheteroaralkyl, 4-10 membered heterocyclyl, 4-10 memberedheterocyclylalkyl, 3-10 membered carbocyclyl, or 3-10 memberedcarbocyclylalkyl, each of which is optionally substituted with 0 to 5occurrences of R⁵. In certain embodiments, Q of Formula (I) istrifluoroacetate. In certain embodiments, Q of Formula (I) istrichloroacetate. In certain embodiments, Q of Formula (I) is NO₂ ⁻. Incertain embodiments, Q of Formula (I) is NO₃ ⁻. In certain embodiments,Q of Formula (I) is H₂PO₄ ⁻. In certain embodiments, Q of Formula (I) isPF₆ ⁻. In certain embodiments, Q of Formula (I) is HF²⁻. In certainembodiments, Q of Formula (I) is HSO₄ ⁻. In certain embodiments, Q ofFormula (I) is SbF₆ ⁻. In certain embodiments, Q of Formula (I) is ClO₄⁻. In certain embodiments, Q of Formula (I) is SO₄ ⁻². In certainembodiments, Q of Formula (I) is (R⁶)SO₃ ⁻. In certain embodiments, Q ofFormula (I) is OTf⁻. In certain embodiments, Q of Formula (I) is OTs⁻.In certain embodiments, Q of Formula (I) is ONf⁻. In certainembodiments, Q of Formula (I) is ONs⁻. In certain embodiments, Q ofFormula (I) is BF₄ ⁻. In certain embodiments, Q of Formula (I) is B(R⁶)₄⁻. In certain embodiments, Q of Formula (I) is B(R⁶)₄ ⁻. In certainembodiments, Q of Formula (I) is fluoro. In certain embodiments, Q ofFormula (I) is chloro. In certain embodiments, Q of Formula (I) isbromo. In certain embodiments, Q of Formula (I) is iodo.

In certain embodiments, A is LiX, MgX₂, ScX₃, ScR⁶ ₃ YX₃, YR⁶ ₃, BR⁶ ₃,BX₃, TiX₄, TiR⁶ ₄, ZrX₄, ZrR⁶ ₄, FeX₃, FeR⁶ ₃, ZnX₂, ZnR⁶ ₂, AlX₃, AlR⁶₃, InX₃, InR⁶ ₃, SiX₄, SiR⁶ ₄, SnX₂, SnR⁶ ₂, SnX₄, SnR⁶ ₄, BiX₃, BiR⁶ ₃,m is 1, and v is 0, wherein X is halogen or Q, and R⁶ is defined asabove. In certain embodiments, A is LiX. In certain embodiments, A isMgX₂. In certain embodiments, A is ScX₃. In certain embodiments, A isScR⁶ ₃. In certain embodiments, A is YX₃. In certain embodiments, A isYR⁶ ₃. In certain embodiments, A is BR⁶ ₃. In certain embodiments, A isBX₃. In certain embodiments, A is TiX₄. In certain embodiments, A isTiR⁶ ₄. In certain embodiments, A is ZrX₄. In certain embodiments, A isZrR⁶ ₄. In certain embodiments, A is AlX₃. In certain embodiments, A isAlR⁶ ₃. In certain embodiments, A is InX₃. In certain embodiments, A isInR⁶ ₃. In certain embodiments, A is SiX₄. In certain embodiments, A isSiR⁶ ₄. In certain embodiments, A is SnX₂. In certain embodiments, A isSnR⁶ ₂. In certain embodiments, A is BiX₃. In certain embodiments, A isBiR⁶ ₃.

In another aspect, the present invention is directed to a compound ofFormula (II):

wherein

S is an organic substrate;

Q is an anion;

R¹ and R² are independently selected from the group consisting of C₁₋₆alkyl, C₆₋₁₀ aryl, C₆₋₁₀ aralkyl, 5-10 membered heteroaryl, 5-10membered heteroaralkyl, 4-10 membered heterocyclyl, 4-10 memberedheterocyclylalkyl, 3-10 membered carbocyclyl, and 3-10 memberedcarbocyclylalkyl, each of which is optionally substituted with 0 to 5occurrences of R⁵;

R³ and R⁴ are independently selected from the group consisting ofhydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, nitro, cyano, halo,C₁₋₆ haloalkyl, C₁₋₆ alkoxy, optionally substituted C₆₋₁₀ aryl,optionally substituted C₆₋₁₀ aralkyl, optionally substituted 5-10membered heteroaryl, optionally substituted 4-10 membered heterocyclyl,optionally substituted 3-10 membered carbocyclyl, optionally substituted4-10 membered heterocyclylalkyl, acyl, —NH₂, —NHR⁷, —N(R⁷)₂, —OH, —SH,—SO₂R⁷, —SOR⁷, —SO₂NR⁷ ₂, and —SR⁷;

R⁷ is independently selected from the group consisting of hydrogen,acyl, optionally substituted aliphatic, optionally substitutedcarbocyclyl, optionally substituted heterocyclyl, optionally substitutedaryl, and optionally substituted heteroaryl, or two R⁷ groups are takentogether with their intervening atoms to form an optionally substitutedheterocyclic ring; and

R⁵ is independently selected from the group consisting of halo, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy,optionally substituted C₆₋₁₀ aryl, optionally substituted 5-10 memberedheteroaryl, optionally substituted 4-10 membered heterocyclyl,optionally substituted 3-10 membered carbocyclyl, nitro, cyano, acyl,—NH₂, —NHR⁷, —N(R⁷)₂, —OH, —SH, —SO₂R⁷, —SOR⁷, —SO₂NR⁷ ₂, and —SR⁷.

In certain embodiments, R¹ and R² of Formula (II) are independentlyC₆₋₁₀ aryl, optionally substituted with 0 to 5 occurrences of R⁵. Incertain embodiments, R¹ and R² of Formula (II) are independently 5-10membered heteroaryl, optionally substituted with 0 to 5 occurrences ofR⁵. In certain embodiments, R¹ and R² of Formula (II) are independently4-10 membered heterocyclyl, optionally substituted with 0 to 5occurrences of R⁵. In certain embodiments, R¹ and R² of Formula (II) areindependently 3-10 membered carbocyclyl, optionally substituted with 0to 5 occurrences of R⁵.

In certain embodiments, the compound of Formula (II) is a compound ofFormula (II-a):

In certain embodiments, the compound of Formula (II) is a compound ofFormula (II-b):

In certain embodiments, R³ of Formula (II) is hydrogen. In certainembodiments, R⁴ of Formula (II) is hydrogen. In certain embodiments,both R³ and R⁴ of Formula (II) are hydrogen.

In certain embodiments, the compound of Formula (II) is a compound ofFormula (II-c):

In certain embodiments, the compound of Formula (II) is a compound ofFormula (II-d):

In certain embodiments, the compound of Formula (II) is a compound ofFormula (II-e):

In certain embodiments, the compound of Formula (II) is a compound ofFormula (II-f):

wherein

each occurrence of R⁸ is independently selected from the groupconsisting of C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, nitro, cyano,halo, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, optionally substituted C₆₋₁₀ aryl,optionally substituted C₆₋₁₀ aralkyl, optionally substituted 5-10membered heteroaryl, optionally substituted 4-10 membered heterocyclyl,optionally substituted 3-10 membered carbocyclyl, optionally substituted4-10 membered heterocyclylalkyl, acyl, —N(R^(8a))₂, —OR^(8a),—CO₂R^(8a), —SO₂R^(8a), —SOR^(8a), —SO₂N(R^(8a))₂, and —SR^(8a);

each occurrence of R⁹ is independently selected from the groupconsisting of C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, nitro, cyano,halo, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, optionally substituted C₆₋₁₀ aryl,optionally substituted C₆₋₁₀ aralkyl, optionally substituted 5-10membered heteroaryl, optionally substituted 4-10 membered heterocyclyl,optionally substituted 3-10 membered carbocyclyl, and optionallysubstituted 4-10 membered heterocyclylalkyl, acyl, —N(R^(9a))₂,—OR^(9a), —CO₂R^(9a), —SO₂R^(9a), —SOR^(9a), —SO₂N(R^(9a))₂, and—SR^(9a);

each occurrence of R^(8a) or R^(9a) is independently selected from thegroup consisting of hydrogen, acyl, optionally substituted aliphatic,optionally substituted carbocyclyl, optionally substituted heterocyclyl,optionally substituted aryl, and optionally substituted heteroaryl, ortwo R^(8a) or R^(9a) groups are taken together with their interveningatoms to form an optionally substituted heterocyclic ring; and

p is 0, 1, 2, or 3.

In certain embodiments, the compound of Formula (II) is a compound ofFormula (II-g):

In certain embodiments, the compound of Formula (II) is a compound ofFormula (II-h):

In certain embodiments, Q of Formula (II) is any suitable counterion. Incertain embodiments, Q of Formula (II) is

halogen (e.g., fluoro, chloro, bromo, or iodo), trifluoroacetate,trichloroacetate, NO₂ ⁻, NO₃ ⁻, H₂PO₄ ⁻, PF₆ ⁻, HF²⁻, HSO₄ ⁻, SbF₆ ⁻,ClO₄ ⁻, SO₄ ⁻², (R⁶)SO₃ ⁻, OTf⁻, OTs⁻, ONf⁻, ONs⁻, BF₄ ⁻, or B(R⁶)₄ ⁻,wherein R⁶ is C₁₋₆ alkyl, —OR⁷, C₆₋₁₀ aryl, C₆₋₁₀ aralkyl, 5-10 memberedheteroaryl, 5-10 membered heteroaralkyl, 4-10 membered heterocyclyl,4-10 membered heterocyclylalkyl, 3-10 membered carbocyclyl, or 3-10membered carbocyclylalkyl, each of which is optionally substituted with0 to 5 occurrences of R⁵. In certain embodiments, Q of Formula (II) is

In certain embodiments, Q of Formula (II) is trifluoroacetate. Incertain embodiments, Q of Formula (II) is trichloroacetate. In certainembodiments, Q of Formula (II) is NO₂ ⁻. In certain embodiments, Q ofFormula (II) is NO₃ ⁻. In certain embodiments, Q of Formula (II) isH₂PO₄ ⁻. In certain embodiments, Q of Formula (II) is PF₆ ⁻. In certainembodiments, Q of Formula (II) is HF²⁻. In certain embodiments, Q ofFormula (II) is HSO₄ ⁻. In certain embodiments, Q of Formula (II) isSbF₆ ⁻. In certain embodiments, Q of Formula (II) is ClO₄ ⁻. In certainembodiments, Q of Formula (II) is SO₄ ⁻². In certain embodiments, Q ofFormula (II) is (R⁶)SO₃ ⁻. In certain embodiments, Q of Formula (II) isOTf⁻. In certain embodiments, Q of Formula (II) is OTs⁻. In certainembodiments, Q of Formula (II) is ONf⁻. In certain embodiments, Q ofFormula (II) is ONs⁻. In certain embodiments, Q of Formula (II) is BF₄⁻. In certain embodiments, Q of Formula (II) is B(R⁶)₄ ⁻. In certainembodiments, Q of Formula (II) is fluoro. In certain embodiments, Q ofFormula (II) is chloro. In certain embodiments, Q of Formula (II) isbromo. In certain embodiments, Q of Formula (II) is iodo.

In another aspect, the present invention is directed to a compound ofFormula (III):

wherein

S is an organic substrate;

R¹ and R² are independently selected from the group consisting of C₁₋₆alkyl, C₆₋₁₀ aryl, C₆₋₁₀ aralkyl, 5-10 membered heteroaryl, 5-10membered heteroaralkyl, 4-10 membered heterocyclyl, 4-10 memberedheterocyclylalkyl, 3-10 membered carbocyclyl, and 3-10 memberedcarbocyclylalkyl, each of which is optionally substituted with 0 to 5occurrences of R⁵;

R³ and R⁴ are independently selected from the group consisting ofhydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, nitro, cyano, halo,C₁₋₆ haloalkyl, C₁₋₆ alkoxy, optionally substituted C₆₋₁₀ aryl,optionally substituted C₆₋₁₀ aralkyl, optionally substituted 5-10membered heteroaryl, optionally substituted 4-10 membered heterocyclyl,optionally substituted 3-10 membered carbocyclyl, optionally substituted4-10 membered heterocyclylalkyl, acyl, —NH₂, —NHR⁷, —N(R⁷)₂, —OH, —SH,—SO₂R⁷, —SOR⁷, —SO₂NR⁷ ₂, and —SR⁷;

R⁷ is independently selected from the group consisting of hydrogen,acyl, optionally substituted aliphatic, optionally substitutedcarbocyclyl, optionally substituted heterocyclyl, optionally substitutedaryl, and optionally substituted heteroaryl, or two R⁷ groups are takentogether with their intervening atoms to form an optionally substitutedheterocyclic ring; and

R⁵ is independently selected from the group consisting of halo, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy,optionally substituted C₆₋₁₀ aryl, optionally substituted 5-10 memberedheteroaryl, optionally substituted 4-10 membered heterocyclyl,optionally substituted 3-10 membered carbocyclyl, nitro, cyano, acyl,—NH₂, —NHR⁷, —N(R⁷)₂, —OH, —SH, —SO₂R⁷, —SOR⁷, —SO₂NR⁷ ₂, and —SR⁷.

In certain embodiments, R¹ and R² of Formula (III) are independentlyC₆₋₁₀ aryl, optionally substituted with 0 to 5 occurrences of R⁵. Incertain embodiments, R¹ and R² of Formula (III) are independently 5-10membered heteroaryl, optionally substituted with 0 to 5 occurrences ofR⁵. In certain embodiments, R¹ and R² of Formula (III) are independently4-10 membered heterocyclyl, optionally substituted with 0 to 5occurrences of R⁵. In certain embodiments, R¹ and R² of Formula (III)are independently 3-10 membered carbocyclyl, optionally substituted with0 to 5 occurrences of R⁵.

In certain embodiments, the compound of Formula (III) is a compound ofFormula (III-a):

In certain embodiments, the compound of Formula (III) is a compound ofFormula (III-b):

In certain embodiments, R³ of Formula (III) is hydrogen. In certainembodiments, R⁴ of Formula (III) is hydrogen. In certain embodiments,both R³ and R⁴ of Formula (III) are hydrogen.

In certain embodiments, the compound of Formula (III) is a compound ofFormula (III-c):

In another aspect, the present invention is directed to a compound ofFormula (IV):

wherein

S is an organic substrate;

D is oxygen or sulfur;

A is hydrogen or a Lewis acid;

R¹ and R² are independently selected from the group consisting of C₁₋₆alkyl, C₆₋₁₀ aryl, C₆₋₁₀ aralkyl, 5-10 membered heteroaryl, 5-10membered heteroaralkyl, 4-10 membered heterocyclyl, 4-10 memberedheterocyclylalkyl, 3-10 membered carbocyclyl, and 3-10 memberedcarbocyclylalkyl, each of which is optionally substituted with 0 to 5occurrences of R⁵;

R³ and R⁴ are independently selected from the group consisting ofhydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, nitro, cyano, halo,C₁₋₆ haloalkyl, C₁₋₆ alkoxy, optionally substituted C₆₋₁₀ aryl,optionally substituted C₆₋₁₀ aralkyl, optionally substituted 5-10membered heteroaryl, optionally substituted 4-10 membered heterocyclyl,optionally substituted 3-10 membered carbocyclyl, optionally substituted4-10 membered heterocyclylalkyl, acyl, —NH₂, —NHR⁷, —N(R⁷)₂, —OH, —SH,—SO₂R⁷, —SOR⁷, —SO₂NR⁷ ₂, and —SR⁷;

R⁷ is independently selected from the group consisting of hydrogen,acyl, optionally substituted aliphatic, optionally substitutedcarbocyclyl, optionally substituted heterocyclyl, optionally substitutedaryl, and optionally substituted heteroaryl, or two R⁷ groups are takentogether with their intervening atoms to form an optionally substitutedheterocyclic ring; and

R⁵ is independently selected from the group consisting of halo, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy,optionally substituted C₆₋₁₀ aryl, optionally substituted 5-10 memberedheteroaryl, optionally substituted 4-10 membered heterocyclyl,optionally substituted 3-10 membered carbocyclyl, nitro, cyano, acyl,—NH₂, —NHR⁷, —N(R⁷)₂, —OH, —SH, —SO₂R⁷, —SOR⁷, —SO₂NR⁷ ₂, and —SR⁷.

In certain embodiments, R¹ and R² of Formula (IV) are independentlyC₆₋₁₀ aryl, optionally substituted with 0 to 5 occurrences of R⁵. Incertain embodiments, R¹ and R² of Formula (IV) are independently 5-10membered heteroaryl, optionally substituted with 0 to 5 occurrences ofR⁵. In certain embodiments, R¹ and R² of Formula (IV) are independently4-10 membered heterocyclyl, optionally substituted with 0 to 5occurrences of R⁵. In certain embodiments, R¹ and R² of Formula (IV) areindependently 3-10 membered carbocyclyl, optionally substituted with 0to 5 occurrences of R⁵.

In certain embodiments, the compound of Formula (IV) is a compound ofFormula (IV-a):

In certain embodiments, the compound of Formula (IV) is a compound ofFormula (IV-b):

In certain embodiments, R³ of Formula (IV-b) is hydrogen. In certainembodiments, R⁴ of Formula (IV-b) is hydrogen. In certain embodiments,both R³ and R⁴ of Formula (IV-b) are hydrogen.

In certain embodiments, the compound of Formula (IV) is a compound ofFormula (IV-c):

In another aspect, the present invention is directed to a compound ofFormula (IV):

wherein

S is an organic substrate;

R¹ and R² are independently selected from the group consisting of C₁₋₆alkyl, C₆₋₁₀ aryl, C₆₋₁₀ aralkyl, 5-10 membered heteroaryl, 5-10membered heteroaralkyl, 4-10 membered heterocyclyl, 4-10 memberedheterocyclylalkyl, 3-10 membered carbocyclyl, and 3-10 memberedcarbocyclylalkyl, each of which is optionally substituted with 0 to 5occurrences of R⁵;

R³ and R⁴ are independently selected from the group consisting ofhydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, nitro, cyano, halo,C₁₋₆ haloalkyl, C₁₋₆ alkoxy, optionally substituted C₆₋₁₀ aryl,optionally substituted C₆₋₁₀ aralkyl, optionally substituted 5-10membered heteroaryl, optionally substituted 4-10 membered heterocyclyl,optionally substituted 3-10 membered carbocyclyl, optionally substituted4-10 membered heterocyclylalkyl, acyl, —NH₂, —NHR⁷, —N(R⁷)₂, —OH, —SH,—SO₂R⁷, —SOR⁷, —SO₂NR⁷ ₂, and —SR⁷;

R⁷ is independently selected from the group consisting of hydrogen,acyl, optionally substituted aliphatic, optionally substitutedcarbocyclyl, optionally substituted heterocyclyl, optionally substitutedaryl, and optionally substituted heteroaryl, or two R⁷ groups are takentogether with their intervening atoms to form an optionally substitutedheterocyclic ring; and

R⁵ is independently selected from the group consisting of halo, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy,optionally substituted C₆₋₁₀ aryl, optionally substituted 5-10 memberedheteroaryl, optionally substituted 4-10 membered heterocyclyl,optionally substituted 3-10 membered carbocyclyl, nitro, cyano, acyl,—NH₂, —NHR⁷, —N(R⁷)₂, —OH, —SH, —SO₂R⁷, —SOR⁷, —SO₂NR⁷ ₂, and —SR⁷.

In certain embodiments, R¹ and R² of Formula (V) are independently C₆₋₁₀aryl, optionally substituted with 0 to 5 occurrences of R⁵. In certainembodiments, R¹ and R² of Formula (V) are independently 5-10 memberedheteroaryl, optionally substituted with 0 to 5 occurrences of R⁵. Incertain embodiments, R¹ and R² of Formula (V) are independently 4-10membered heterocyclyl, optionally substituted with 0 to 5 occurrences ofR⁵. In certain embodiments, R¹ and R² of Formula (V) are independently3-10 membered carbocyclyl, optionally substituted with 0 to 5occurrences of R⁵.

In certain embodiments, the compound of Formula (V) is a compound ofFormula (V-a):

In certain embodiments, the compound of Formula (V) is a compound ofFormula (V-b):

In certain embodiments, R³ of Formula (V-b) is hydrogen. In certainembodiments, R⁴ of Formula (V-b) is hydrogen. In certain embodiments,both R³ and R⁴ of Formula (V-b) are hydrogen.

In certain embodiments, the compound of Formula (V) is a compound ofFormula (V-c):

In another aspect, the present invention is directed to a compound ofFormula (VI):

wherein

Q is an anion;

R¹ and R² are independently selected from the group consisting of C₁₋₆alkyl, C₆₋₁₀ aryl, C₆₋₁₀ aralkyl, 5-10 membered heteroaryl, 5-10membered heteroaralkyl, 4-10 membered heterocyclyl, 4-10 memberedheterocyclylalkyl, 3-10 membered carbocyclyl, and 3-10 memberedcarbocyclylalkyl, each of which is optionally substituted with 0 to 5occurrences of R⁵;

R³ and R⁴ are independently selected from the group consisting ofhydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, nitro, cyano, halo,C₁₋₆ haloalkyl, C₁₋₆ alkoxy, optionally substituted C₆₋₁₀ aryl,optionally substituted C₆₋₁₀ aralkyl, optionally substituted 5-10membered heteroaryl, optionally substituted 4-10 membered heterocyclyl,optionally substituted 3-10 membered carbocyclyl, optionally substituted4-10 membered heterocyclylalkyl, acyl, —NH₂, —NHR⁷, —N(R⁷)₂, —OH, —SH,—SO₂R⁷, —SOR⁷, —SO₂NR⁷ ₂, and —SR⁷;

R⁷ is independently selected from the group consisting of hydrogen,acyl, optionally substituted aliphatic, optionally substitutedcarbocyclyl, optionally substituted heterocyclyl, optionally substitutedaryl, and optionally substituted heteroaryl, or two R⁷ groups are takentogether with their intervening atoms to form an optionally substitutedheterocyclic ring; and

R⁵ is independently selected from the group consisting of halo, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy,optionally substituted C₆₋₁₀ aryl, optionally substituted 5-10 memberedheteroaryl, optionally substituted 4-10 membered heterocyclyl,optionally substituted 3-10 membered carbocyclyl, nitro, cyano, acyl,—NH₂, —NHR⁷, —N(R⁷)₂, —OH, —SH, —SO₂R⁷, —SOR⁷, —SO₂NR⁷ ₂, and —SR⁷;

each occurrence of R⁸ is independently selected from the groupconsisting of C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, nitro, cyano,halo, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, optionally substituted C₆₋₁₀ aryl,optionally substituted C₆₋₁₀ aralkyl, optionally substituted 5-10membered heteroaryl, optionally substituted 4-10 membered heterocyclyl,optionally substituted 3-10 membered carbocyclyl, optionally substituted4-10 membered heterocyclylalkyl, acyl, —N(R^(8a))₂, —OR^(8a),—CO₂R^(8a), —SO₂R^(8a), —SOR^(8a), —SO₂N(R^(8a))₂, and —SR^(8a);

each occurrence of R⁹ is independently selected from the groupconsisting of C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, nitro, cyano,halo, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, optionally substituted C₆₋₁₀ aryl,optionally substituted C₆₋₁₀ aralkyl, optionally substituted 5-10membered heteroaryl, optionally substituted 4-10 membered heterocyclyl,optionally substituted 3-10 membered carbocyclyl, and optionallysubstituted 4-10 membered heterocyclylalkyl, acyl, —N(R^(9a))₂,—OR^(9a), —CO₂R^(9a), —SO₂R^(9a), —SOR^(9a), —SO₂N(R^(9a))₂, and—SR^(9a);

each occurrence of R^(8a) or R^(9a) is independently selected from thegroup consisting of hydrogen, acyl, optionally substituted aliphatic,optionally substituted carbocyclyl, optionally substituted heterocyclyl,optionally substituted aryl, and optionally substituted heteroaryl, ortwo R^(8a) or R^(9a) groups are taken together with their interveningatoms to form an optionally substituted heterocyclic ring; and

p is 0, 1, 2, or 3.

In certain embodiments, R¹ and R² of Formula (VI) are independentlyC₆₋₁₀ aryl, optionally substituted with 0 to 5 occurrences of R⁵. Incertain embodiments, R¹ and R² of Formula (VI) are independently 5-10membered heteroaryl, optionally substituted with 0 to 5 occurrences ofR⁵. In certain embodiments, R¹ and R² of Formula (VI) are independently4-10 membered heterocyclyl, optionally substituted with 0 to 5occurrences of R⁵. In certain embodiments, R¹ and R² of Formula (VI) areindependently 3-10 membered carbocyclyl, optionally substituted with 0to 5 occurrences of R⁵.

In certain embodiments, the compound of Formula (VI) is a compound ofFormula (VI-a):

In certain embodiments, the compound of Formula (VI) is a compound ofFormula (VI-b):

In certain embodiments, R³ of Formula (VI) is hydrogen. In certainembodiments, R⁴ of Formula (VI) is hydrogen. In certain embodiments,both R³ and R⁴ of Formula (VI) are hydrogen.

In certain embodiments, the compound of Formula (VI) is a compound ofFormula (VI-c):

In certain embodiments, the compound of Formula (VI) is a compound ofFormula (VI-d):

In certain embodiments, the compound of Formula (VI) is a compound ofFormula (VI-e):

In certain embodiments, the compound of Formula (VI) is a compound ofFormula (VI-f):

In certain embodiments, the compound of Formula (VI) is a compound ofFormula (VI-g):

In certain embodiments, the compound of Formula (VI) is a compound ofFormula (VI-h):

In certain embodiments, Q of Formula (VI) is any suitable counterion. Incertain embodiments, Q of Formula (VI) is

halogen (e.g., fluoro, chloro, bromo, or iodo), trifluoroacetate,trichloroacetate, NO₂ ⁻, NO₃ ⁻, H₂PO₄ ⁻, PF₆ ⁻, HF²⁻, HSO₄ ⁻, SbF₆ ⁻,ClO₄ ⁻, SO₄ ⁻², (R⁶)SO₃ ⁻, OTf⁻, OTs⁻, ONf⁻, ONs⁻, BF₄ ⁻, or B(R⁶)₄ ⁻,wherein R⁶ is C₁₋₆ alkyl, —OR⁷, C₆₋₁₀ aryl, C₆₋₁₀ aralkyl, 5-10 memberedheteroaryl, 5-10 membered heteroaralkyl, 4-10 membered heterocyclyl,4-10 membered heterocyclylalkyl, 3-10 membered carbocyclyl, or 3-10membered carbocyclylalkyl, each of which is optionally substituted with0 to 5 occurrences of R⁵. In certain embodiments, Q of Formula (VI) is

In certain embodiments, Q of Formula (VI) is trifluoroacetate. Incertain embodiments, Q of Formula (VI) is trichloroacetate. In certainembodiments, Q of Formula (VI) is NO₂ ⁻. In certain embodiments, Q ofFormula (VI) is NO₃ ⁻. In certain embodiments, Q of Formula (VI) isH₂PO₄ ⁻. In certain embodiments, Q of Formula (VI) is PF₆ ⁻. In certainembodiments, Q of Formula (VI) is HF²⁻. In certain embodiments, Q ofFormula (VI) is HSO₄ ⁻. In certain embodiments, Q of Formula (VI) isSbF₆ ⁻. In certain embodiments, Q of Formula (VI) is ClO₄ ⁻. In certainembodiments, Q of Formula (VI) is SO₄ ⁻². In certain embodiments, Q ofFormula (VI) is (R⁶)SO₃ ⁻. In certain embodiments, Q of Formula (VI) isOTf⁻. In certain embodiments, Q of Formula (VI) is OTs⁻. In certainembodiments, Q of Formula (VI) is ONf⁻. In certain embodiments, Q ofFormula (VI) is ONs⁻. In certain embodiments, Q of Formula (VI) is BF₄⁻. In certain embodiments, Q of Formula (VI) is B(R⁶)₄ ⁻. In certainembodiments, Q of Formula (VI) is B(R⁶)₄ ⁻. In certain embodiments, Q ofFormula (VI) is fluoro. In certain embodiments, Q of Formula (VI) ischloro. In certain embodiments, Q of Formula (VI) is bromo. In certainembodiments, Q of Formula (VI) is iodo.

In another aspect, the present invention is directed to a method ofreplacing a hydroxyl group on an organic compound with a fluorine atom,the method comprising contacting a compound of Formula (I):

wherein

D is oxygen or sulfur;

A is hydrogen or a Lewis acid;

Q is an anion;

R¹ and R² are independently selected from the group consisting of C₁₋₆alkyl, C₆₋₁₀ aryl, C₆₋₁₀ aralkyl, 5-10 membered heteroaryl, 5-10membered heteroaralkyl, 4-10 membered heterocyclyl, 4-10 memberedheterocyclylalkyl, 3-10 membered carbocyclyl, and 3-10 memberedcarbocyclylalkyl, each of which is optionally substituted with 0 to 5occurrences of R⁵;

R³ and R⁴ are independently selected from the group consisting ofhydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, nitro, cyano, halo,C₁₋₆ haloalkyl, C₁₋₆ alkoxy, optionally substituted C₆₋₁₀ aryl,optionally substituted C₆₋₁₀ aralkyl, optionally substituted 5-10membered heteroaryl, optionally substituted 4-10 membered heterocyclyl,optionally substituted 3-10 membered carbocyclyl, optionally substituted4-10 membered heterocyclylalkyl, acyl, —NH₂, —NHR⁷, —N(R⁷)₂, —OH, —SH,—SO₂R⁷, —SOR⁷, —SO₂NR⁷ ₂, and —SR⁷;

R⁷ is independently selected from the group consisting of hydrogen,acyl, optionally substituted aliphatic, optionally substitutedcarbocyclyl, optionally substituted heterocyclyl, optionally substitutedaryl, and optionally substituted heteroaryl, or two R⁷ groups are takentogether with their intervening atoms to form an optionally substitutedheterocyclic ring;

R⁵ is independently selected from the group consisting of halo, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy,optionally substituted C₆₋₁₀ aryl, optionally substituted 5-10 memberedheteroaryl, optionally substituted 4-10 membered heterocyclyl,optionally substituted 3-10 membered carbocyclyl, nitro, cyano, acyl,—NH₂, —NHR⁷, —N(R⁷)₂, —OH, —SH, —SO₂R⁷, —SOR⁷, —SO₂NR⁷ ₂, and —SR⁷;

t is the anion charge number, ranging from 1-3;

v is 0-3;

m is 1-5;

with an organic compound under conditions sufficient to fluorinate theorganic compound, thereby providing a fluorinated organic compound.

In certain embodiments of the method, R¹ and R² of Formula (I) areindependently C₆₋₁₀ aryl, optionally substituted with 0 to 5 occurrencesof R⁵. In certain embodiments of the method, R¹ and R² of Formula (I)are independently 5-10 membered heteroaryl, optionally substituted with0 to 5 occurrences of R⁵. In certain embodiments of the method, R¹ andR² of Formula (I) are independently 4-10 membered heterocyclyl,optionally substituted with 0 to 5 occurrences of R⁵. In certainembodiments of the method, R¹ and R² of Formula (I) are independently3-10 membered carbocyclyl, optionally substituted with 0 to 5occurrences of R⁵.

In certain embodiments, the method comprises contacting a compound ofFormula (I-c):

with an organic compound under conditions sufficient to fluorinate theorganic compound, thereby providing a fluorinated organic compound.

In certain embodiments, the fluorinated organic compound comprises ¹⁸F.In certain embodiments, the hydroxyl group-containing organic substrateis aliphatic. In certain embodiments, the hydroxyl group-containingorganic substrate is aryl. In certain embodiments, the hydroxylgroup-containing organic substrate is vinyl. In certain embodiments, thehydroxyl group-containing organic substrate is heteroaryl. In certainembodiments, the hydroxyl group-containing organic substrate comprises atautomer of a heteroaryl hydroxyl group. In certain embodiments, thehydroxyl group-containing organic substrate is heterocyclic. In certainembodiments, the hydroxyl group-containing organic substrate comprises atautomer of a heterocyclic hydroxyl group. In certain embodiments, themethod further comprises a source of fluorine. In certain embodiments,the fluorine source is a fluoride salt. In certain embodiments, thefluorine source is a sodium, potassium, or cesium fluoride salt. Incertain embodiments, the fluorine source is the counter ion Q. Incertain embodiments, the method comprises approximately 1-10 equivalentsof a fluorine source. In certain embodiments, the method comprisesapproximately 1-5 equivalents of a fluorine source. In certainembodiments, the method comprises approximately 5-10 equivalents of afluorine source. In certain embodiments, the method comprisesapproximately 3-5 equivalents of a fluorine source. In certainembodiments, the method comprises greater than 10 equivalents of afluorine source. In certain embodiments, the fluorine source comprises¹⁸F. In certain embodiments, the step of contacting is performed in thepresence of an organic or inorganic base. In certain embodiments, thebase is an inorganic base. In certain embodiments, the base is sodium,potassium, or cesium carbonate. In certain embodiments, the methodcomprises approximately 1-10 equivalents of a base. In certainembodiments, the method comprises approximately 1-5 equivalents of abase. In certain embodiments, the method comprises approximately 5-10equivalents of a base. In certain embodiments, the method comprisesapproximately 3-5 equivalents of a base. In certain embodiments, themethod comprises greater than 10 equivalents of a base. In certainembodiments, the step of contacting comprises heating the compound ofFormula (I) and the hydroxyl group-containing organic substrate to atemperature of approximately 80-140° C. In certain embodiments, the stepof contacting comprises heating the compound of Formula (I) and thehydroxyl group-containing organic substrate to a temperature ofapproximately 100-120° C. In certain embodiments, the step of contactingcomprises heating the compound of Formula (I) and the hydroxylgroup-containing organic substrate to a temperature of about 110° C. Incertain embodiments, the step of contacting lasts 5 minutes or less. Incertain embodiments, the step of contacting lasts 15 minutes or less. Incertain embodiments, the step of contacting lasts 30 minutes or less. Incertain embodiments, the step of contacting lasts 1 hour or less. Incertain embodiments, the step of contacting more than 1 hour. In certainembodiments, the method further comprises purifying the fluorinatedorganic compound. In certain embodiments, said method is incorporatedinto an automated process by which PET imaging agents are produced viareaction of hydroxyl group containing organic compounds with a compoundof Formula (I), and a source of ¹⁸F. In certain embodiments, the yieldof the fluorinated organic compound from the organic compound is atleast about 5%. In certain embodiments, the yield of the fluorinatedorganic compound from the organic compound is at least about 10%. Incertain embodiments, the yield of the fluorinated organic compound fromthe organic compound is at least about 15%. In certain embodiments, theyield of the fluorinated organic compound from the organic compound isat least about 20%. In certain embodiments, the yield of the fluorinatedorganic compound from the organic compound is at least about 25%. Incertain embodiments, the yield of the fluorinated organic compound fromthe organic compound is at least about 30%. In certain embodiments, theyield of the fluorinated organic compound from the organic compound isat least about 35%. In certain embodiments, the yield of the fluorinatedorganic compound from the organic compound is at least about 40%. Incertain embodiments, the yield of the fluorinated organic compound fromthe organic compound is at least about 45%. In certain embodiments, theyield of the fluorinated organic compound from the organic compound isat least about 50%. In certain embodiments, the yield of the fluorinatedorganic compound from the organic compound is at least about 55%. Incertain embodiments, the yield of the fluorinated organic compound fromthe organic compound is at least about 60%. In certain embodiments, theyield of the fluorinated organic compound from the organic compound isat least about 65%. In certain embodiments, the yield of the fluorinatedorganic compound from the organic compound is at least about 70%. Incertain embodiments, the yield of the fluorinated organic compound fromthe organic compound is at least about 75%. In certain embodiments, theyield of the fluorinated organic compound from the organic compound isat least about 80%. In certain embodiments, the yield of the fluorinatedorganic compound from the organic compound is at least about 85%. Incertain embodiments, the yield of the fluorinated organic compound fromthe organic compound is at least about 90%. In certain embodiments, theyield of the fluorinated organic compound from the organic compound isat least about 95%. In certain embodiments, the yield of the fluorinatedorganic compound from the organic compound is greater than 95%.

In another aspect, the present invention provides methods of replacing ahydroxyl group on an organic compound with a fluorine atom, the methodcomprising exchanging an anion Q of a compound of Formula (II):

wherein

S is an organic substrate;

Q is an anion;

R¹ and R² are independently selected from the group consisting of C₁₋₆alkyl, C₆₋₁₀ aryl, C₆₋₁₀ aralkyl, 5-10 membered heteroaryl, 5-10membered heteroaralkyl, 4-10 membered heterocyclyl, 4-10 memberedheterocyclylalkyl, 3-10 membered carbocyclyl, and 3-10 memberedcarbocyclylalkyl, each of which is optionally substituted with 0 to 5occurrences of R⁵;

R³ and R⁴ are independently selected from the group consisting ofhydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, nitro, cyano, halo,C₁₋₆ haloalkyl, C₁₋₆ alkoxy, optionally substituted C₆₋₁₀ aryl,optionally substituted C₆₋₁₀ aralkyl, optionally substituted 5-10membered heteroaryl, optionally substituted 4-10 membered heterocyclyl,optionally substituted 3-10 membered carbocyclyl, optionally substituted4-10 membered heterocyclylalkyl, acyl, —NH₂, —NHR⁷, —N(R⁷)₂, —OH, —SH,—SO₂R⁷, —SOR⁷, —SO₂NR⁷ ₂, and —SR⁷;

R⁷ is independently selected from the group consisting of hydrogen,acyl, optionally substituted aliphatic, optionally substitutedcarbocyclyl, optionally substituted heterocyclyl, optionally substitutedaryl, and optionally substituted heteroaryl, or two R⁷ groups are takentogether with their intervening atoms to form an optionally substitutedheterocyclic ring; and

R⁵ is independently selected from the group consisting of halo, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy,optionally substituted C₆₋₁₀ aryl, optionally substituted 5-10 memberedheteroaryl, optionally substituted 4-10 membered heterocyclyl,optionally substituted 3-10 membered carbocyclyl, nitro, cyano, acyl,—NH₂, —NHR⁷, —N(R⁷)₂, —OH, —SH, —SO₂R⁷, —SOR⁷, —SO₂NR⁷ ₂, and —SR⁷, witha fluoride or HF₂ anion. In certain embodiments, the ion exchangereaction is carried out using an anion exchange resin or anion exchangechromatography.

In certain embodiments of the method, R¹ and R² of Formula (II) areindependently C₆₋₁₀ aryl, optionally substituted with 0 to 5 occurrencesof R⁵. In certain embodiments of the method, R¹ and R² of Formula (II)are independently 5-10 membered heteroaryl, optionally substituted with0 to 5 occurrences of R⁵. In certain embodiments of the method, R¹ andR² of Formula (II) are independently 4-10 membered heterocyclyl,optionally substituted with 0 to 5 occurrences of R⁵. In certainembodiments of the method, R¹ and R² of Formula (II) are independently3-10 membered carbocyclyl, optionally substituted with 0 to 5occurrences of R⁵.

In certain embodiments, the method of replacing a hydroxyl group on anorganic compound with a fluorine atom comprises exchanging a chlorideanion of a compound of Formula (II-e):

with a fluoride or HF₂ anion.

In certain embodiments, the method of replacing a hydroxyl group on anorganic compound with a fluorine atom comprises exchanging a phenolateanion of a compound of Formula (II-f):

with a fluoride or HF₂ anion.

In certain embodiments, the fluorinated organic compound comprises ¹⁸F.In certain embodiments, the hydroxyl group-containing organic substrateis aliphatic. In certain embodiments, the hydroxyl group-containingorganic substrate is aryl. In certain embodiments, the hydroxylgroup-containing organic substrate is vinyl. In certain embodiments, thehydroxyl group-containing organic substrate is heteroaryl. In certainembodiments, the hydroxyl group-containing organic substrate comprises atautomer of a heteroaryl hydroxyl group. In certain embodiments, thehydroxyl group-containing organic substrate is heterocyclic. In certainembodiments, the hydroxyl group-containing organic substrate comprises atautomer of a heterocyclic hydroxyl group. In certain embodiments, themethod further comprises a source of fluorine. In certain embodiments,the fluorine source is a fluoride salt. In certain embodiments, thefluorine source is a sodium, potassium, or cesium fluoride salt. Incertain embodiments, the fluorine source is the counter ion Q. Incertain embodiments, the method comprises approximately 1-10 equivalentsof a fluorine source. In certain embodiments, the method comprisesapproximately 1-5 equivalents of a fluorine source. In certainembodiments, the method comprises approximately 5-10 equivalents of afluorine source. In certain embodiments, the method comprisesapproximately 3-5 equivalents of a fluorine source. In certainembodiments, the method comprises greater than 10 equivalents of afluorine source. In certain embodiments, the fluorine source comprises¹⁸F. In certain embodiments, the step of contacting is performed in thepresence of an organic or inorganic base. In certain embodiments, thebase is an inorganic base. In certain embodiments, the base is sodium,potassium, or cesium carbonate. In certain embodiments, the methodcomprises approximately 1-10 equivalents of a base. In certainembodiments, the method comprises approximately 1-5 equivalents of abase. In certain embodiments, the method comprises approximately 5-10equivalents of a base. In certain embodiments, the method comprisesapproximately 3-5 equivalents of a base. In certain embodiments, themethod comprises greater than 10 equivalents of a base. In certainembodiments, the step of contacting comprises heating the compound ofFormula (II) and a fluorine source. In certain embodiments, the compoundof Formula (II) and the fluorine source are heated to a temperature ofapproximately 80-140° C. In certain embodiments, the compound of Formula(II) and the fluorine source are heated to a temperature ofapproximately 100-120° C. In certain embodiments, the compound ofFormula (II) and the fluorine source are heated to a temperature ofabout 110° C. In certain embodiments, the step of fluorinating acompound of Formula (II) lasts 5 minutes or less. In certainembodiments, the step of the step of fluorinating a compound of Formula(II) lasts 15 minutes or less. In certain embodiments, the step of thestep of fluorinating a compound of Formula (II) lasts 30 minutes orless. In certain embodiments, the step of the step of fluorinating acompound of Formula (II) lasts 1 hour or less. In certain embodiments,the step of contacting lasts more than 1 hour. In certain embodiments,the step of fluorinating a compound of Formula (II) or exchanging theanion Q is carried out in a mixture of water and an organic solvent. Incertain embodiments, the step of fluorinating a compound of Formula (II)or exchanging the anion Q is carried out in a mixture of water anddioxane. In certain embodiments, the method further comprises purifyingthe fluorinated organic compound. In certain embodiments, said method isincorporated into an automated process by which PET imaging agents areproduced via reaction of a compound of Formula (II) and a source of ¹⁸F.In certain embodiments, the yield of the fluorinated organic compoundfrom the organic compound is at least about 5%. In certain embodiments,the yield of the fluorinated organic compound from the organic compoundis at least about 10%. In certain embodiments, the yield of thefluorinated organic compound from the organic compound is at least about15%. In certain embodiments, the yield of the fluorinated organiccompound from the organic compound is at least about 20%. In certainembodiments, the yield of the fluorinated organic compound from theorganic compound is at least about 25%. In certain embodiments, theyield of the fluorinated organic compound from the organic compound isat least about 30%. In certain embodiments, the yield of the fluorinatedorganic compound from the organic compound is at least about 35%. Incertain embodiments, the yield of the fluorinated organic compound fromthe organic compound is at least about 40%. In certain embodiments, theyield of the fluorinated organic compound from the organic compound isat least about 45%. In certain embodiments, the yield of the fluorinatedorganic compound from the organic compound is at least about 50%. Incertain embodiments, the yield of the fluorinated organic compound fromthe organic compound is at least about 55%. In certain embodiments, theyield of the fluorinated organic compound from the organic compound isat least about 60%. In certain embodiments, the yield of the fluorinatedorganic compound from the organic compound is at least about 65%. Incertain embodiments, the yield of the fluorinated organic compound fromthe organic compound is at least about 70%. In certain embodiments, theyield of the fluorinated organic compound from the organic compound isat least about 75%. In certain embodiments, the yield of the fluorinatedorganic compound from the organic compound is at least about 80%. Incertain embodiments, the yield of the fluorinated organic compound fromthe organic compound is at least about 85%. In certain embodiments, theyield of the fluorinated organic compound from the organic compound isat least about 90%. In certain embodiments, the yield of the fluorinatedorganic compound from the organic compound is at least about 95%. Incertain embodiments, the yield of the fluorinated organic compound fromthe organic compound is greater than 95%.

In certain embodiments, the method of replacing a hydroxyl group on anorganic compound with a fluorine atom comprises exchanging an anion Q ofa compound of Formula (II) with a fluoride or HF₂ anion. In certainembodiments, the ion exchange reaction is carried out using an anionexchange resin or anion exchange chromatography. In certain embodimentsthe anion exchange medium is a weak anion exchange resin. In certainembodiments, the anion exchange medium comprises primary, secondary, ortertiary amine functional groups. In certain embodiments, the anionexchange medium is Amberlite® CR5550, Amberlite® FPA51, Amberlite®FPA53, Amberlite® FPA54, Amberlite® FPA55, Amberlite® IRA-67, Amberlite®IRA-67RF, Amberlite® IRA-70RF, Amberlite® IRA-96, Amberlite® IRA-96RF,Amberlite® IRA-96SB, Amberlite® IRA743, Amberlyst® A21, Amberlyst® A23,Diaion® WA10, Diaion® WA30, Dowex® 66, Dowex® 66RF, Dowex® Marathon®WBA, Dowex® Marathon® WBA-2, Dowex® Monosphere® 66, Dowex® Monosphere®77, Dowex® WGR-2, Dowex® Upcore Mono WB-500, Duolite® A7, Duolite® A568,Lewatit® MonoPlus MP 64, Lewatit® MP-62, Lewatit® VP OC 1065, Toyopearl®DEAE-650M, or TSKgel®. In certain embodiments the anion exchange mediumis a strong anion exchange resin. In certain embodiments, the anionexchange medium comprises quaternary ammonium functional groups. Incertain embodiments, the anion exchange medium is Amberjet® 4200,Amberjet® 4600, Amberjet® 9000, Amberjet® 9800, Amberjet® UP4000,Amberlite® FPA40, Amberlite® FPA42, Amberlite® FPA90, Amberlite® FPA91,Amberlite® FPA98, Amberlite® IRA-400, Amberlite® IRA-402, Amberlite®IRA-405, Amberlite® IRA-410, Amberlite® IRA-458, Amberlite® IRA-458RF,Amberlite® IRA-478, Amberlite® IRA-743, Amberlite® IRA-900, Amberlite®IRA-900RF, Amberlite® IRA-910, Amberlite® IRA-958, Amberlite® IRN-78,Amberlite® IRN-9766, Amberlyst® A26, Ambersep® 400, Ambersep® 4400,Ambersep® 4550, Ambersep® 900, Ambersep® 920U, Ambersep® 920UHC,Ambersep® 920UXL, Ambersep® 940U, Diaion® HPA25, Dowex® 1X2, Dowex® 1X4,Dowex® 1X8, Dowex® 21K, Dowex® 22, Dowex® 2X8, Dowex® 550A, Dowex®Marathon®, Dowex® Marathon® A, Dowex® Marathon® A2, Dowex® Marathon® 11,Dowex® Marathon® MSA-1, Dowex® Marathon® MSA-2, Dowex® Monosphere® 550A,Dowex® Monosphere® 550A UPW, Dowex® RPU, Dowex® SBR-C, Dowex® UpcoreMono A2-500, Dowex® Upcore Mono A-500, Dowex® Upcore Mono A-625, Dowex®Upcore Mono MA-600, Dowex® XZ 91419, Imac® HP555, Lewatit® MonoPlus M500, Lewatit® MP-64, QAE Sephadex® A-50, QAE Sephadex® A-25, Toyopearl®QAE-550C, Toyopearl® SuperQ-650M, Chromafix®, or Chromabond® PS. Incertain embodiments, the anion exchange medium is apolystyrene-bicarbonate resin. In order to facilitate exchange of theanion Q, a solution of a compound of Formula (II) is passed over anionexchange medium or through a column containing anion exchange mediumwhich is infused with fluoride or HF₂ anions. In certain embodiments,between approximately 5 and 100 mg of anion exchange media is used. Incertain embodiments, between approximately 10 and 50 mg of anionexchange media is used. In certain embodiments, approximately 30 mg ofanion exchange media is used. In certain embodiments, betweenapproximately 2 and 20 micromoles of a compound of Formula (II) is used.In certain embodiments, between approximately 5 and 10 micromoles of acompound of Formula (II) is used. In certain embodiments, approximately8 micromoles of a compound of Formula (II) is used. In certainembodiments, the compound of Formula (II) is passed over anion exchangemedium or through a column containing anion exchange medium usingbetween 0.1 and 10 ml of solvent. In certain embodiments, the compoundof Formula (II) is passed over anion exchange medium or through a columncontaining anion exchange medium using between 0.2 and 1 ml of solvent.In certain embodiments, the compound of Formula (II) is passed overanion exchange medium or through a column containing anion exchangemedium using about 5 ml of solvent.

In another aspect, the present invention is directed to a method ofproducing a compound of Formula (II):

wherein

S is an organic substrate;

Q is an anion;

R¹ and R² are independently selected from the group consisting of C₁₋₆alkyl, C₆₋₁₀ aryl, C₆₋₁₀ aralkyl, 5-10 membered heteroaryl, 5-10membered heteroaralkyl, 4-10 membered heterocyclyl, 4-10 memberedheterocyclylalkyl, 3-10 membered carbocyclyl, and 3-10 memberedcarbocyclylalkyl, each of which is optionally substituted with 0 to 5occurrences of R⁵;

R³ and R⁴ are independently selected from the group consisting ofhydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, nitro, cyano, halo,C₁₋₆ haloalkyl, C₁₋₆ alkoxy, optionally substituted C₆₋₁₀ aryl,optionally substituted C₆₋₁₀ aralkyl, optionally substituted 5-10membered heteroaryl, optionally substituted 4-10 membered heterocyclyl,optionally substituted 3-10 membered carbocyclyl, optionally substituted4-10 membered heterocyclylalkyl, acyl, —NH₂, —NHR⁷, —N(R⁷)₂, —OH, —SH,—SO₂R⁷, —SOR⁷, —SO₂NR⁷ ₂, and —SR⁷;

R⁷ is independently selected from the group consisting of hydrogen,acyl, optionally substituted aliphatic, optionally substitutedcarbocyclyl, optionally substituted heterocyclyl, optionally substitutedaryl, and optionally substituted heteroaryl, or two R⁷ groups are takentogether with their intervening atoms to form an optionally substitutedheterocyclic ring; and

R⁵ is independently selected from the group consisting of halo, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy,optionally substituted C₆₋₁₀ aryl, optionally substituted 5-10 memberedheteroaryl, optionally substituted 4-10 membered heterocyclyl,optionally substituted 3-10 membered carbocyclyl, nitro, cyano, acyl,—NH₂, —NHR⁷, —N(R⁷)₂, —OH, —SH, —SO₂R⁷, —SOR⁷, —SO₂NR⁷ ₂, and —SR⁷,

the method comprising contacting a compound of Formula (VI):

wherein

Q is an anion;

R¹ and R² are independently selected from the group consisting of C₁₋₆alkyl, C₆₋₁₀ aryl, C₆₋₁₀ aralkyl, 5-10 membered heteroaryl, 5-10membered heteroaralkyl, 4-10 membered heterocyclyl, 4-10 memberedheterocyclylalkyl, 3-10 membered carbocyclyl, and 3-10 memberedcarbocyclylalkyl, each of which is optionally substituted with 0 to 5occurrences of R⁵;

R³ and R⁴ are independently selected from the group consisting ofhydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, nitro, cyano, halo,C₁₋₆ haloalkyl, C₁₋₆ alkoxy, optionally substituted C₆₋₁₀ aryl,optionally substituted C₆₋₁₀ aralkyl, optionally substituted 5-10membered heteroaryl, optionally substituted 4-10 membered heterocyclyl,optionally substituted 3-10 membered carbocyclyl, optionally substituted4-10 membered heterocyclylalkyl, acyl, —NH₂, —NHR⁷, —N(R⁷)₂, —OH, —SH,—SO₂R⁷, —SOR⁷, —SO₂NR⁷ ₂, and —SR⁷;

R⁷ is independently selected from the group consisting of hydrogen,acyl, optionally substituted aliphatic, optionally substitutedcarbocyclyl, optionally substituted heterocyclyl, optionally substitutedaryl, and optionally substituted heteroaryl, or two R⁷ groups are takentogether with their intervening atoms to form an optionally substitutedheterocyclic ring; and

R⁵ is independently selected from the group consisting of halo, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy,optionally substituted C₆₋₁₀ aryl, optionally substituted 5-10 memberedheteroaryl, optionally substituted 4-10 membered heterocyclyl,optionally substituted 3-10 membered carbocyclyl, nitro, cyano, acyl,—NH₂, —NHR⁷, —N(R⁷)₂, —OH, —SH, —SO₂R⁷, —SOR⁷, —SO₂NR⁷ ₂, and —SR⁷;

each occurrence of R⁸ is independently selected from the groupconsisting of C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, nitro, cyano,halo, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, optionally substituted C₆₋₁₀ aryl,optionally substituted C₆₋₁₀ aralkyl, optionally substituted 5-10membered heteroaryl, optionally substituted 4-10 membered heterocyclyl,optionally substituted 3-10 membered carbocyclyl, optionally substituted4-10 membered heterocyclylalkyl, acyl, —N(R^(8a))₂, —OR^(8a),—CO₂R^(8a), —SO₂R^(8a), —SOR^(8a), —SO₂N(R^(8a))₂, and —SR^(8a);

each occurrence of R⁹ is independently selected from the groupconsisting of C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, nitro, cyano,halo, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, optionally substituted C₆₋₁₀ aryl,optionally substituted C₆₋₁₀ aralkyl, optionally substituted 5-10membered heteroaryl, optionally substituted 4-10 membered heterocyclyl,optionally substituted 3-10 membered carbocyclyl, and optionallysubstituted 4-10 membered heterocyclylalkyl, acyl, —N(R^(9a))₂,—OR^(9a), —CO₂R^(9a), —SO₂R^(9a), —SOR^(9a), —SO₂N(R^(9a))₂, and—SR^(9a);

each occurrence of R^(8a) or R^(9a) is independently selected from thegroup consisting of hydrogen, acyl, optionally substituted aliphatic,optionally substituted carbocyclyl, optionally substituted heterocyclyl,optionally substituted aryl, and optionally substituted heteroaryl, ortwo R^(8a) or R^(9a) groups are taken together with their interveningatoms to form an optionally substituted heterocyclic ring; and

p is 0, 1, 2, or 3, with a hydroxyl group-containing organic substrateand exchanging

In certain embodiments of the method, R¹ and R² of Formula (II) and (IV)are independently C₆₋₁₀ aryl, optionally substituted with 0 to 5occurrences of R⁵. In certain embodiments of the method, R¹ and R² ofFormula (II) and (IV) are independently 5-10 membered heteroaryl,optionally substituted with 0 to 5 occurrences of R⁵. In certainembodiments of the method, R¹ and R² of Formula (II) and (IV) areindependently 4-10 membered heterocyclyl, optionally substituted with 0to 5 occurrences of R⁵. In certain embodiments of the method, R¹ and R²of Formula (II) and (IV) are independently 3-10 membered carbocyclyl,optionally substituted with 0 to 5 occurrences of R⁵.

In certain embodiments, the method further comprises the step ofreplacing a hydroxyl group of an organic compound with a fluorine atomto prepare a fluorinated organic compound. In certain embodiments, thefluorinated organic compound comprises ¹⁸F. In certain embodiments, thehydroxyl group-containing organic compound is aliphatic. In certainembodiments, the hydroxyl group-containing organic substrate is aryl. Incertain embodiments, the hydroxyl group-containing organic substrate isvinyl. In certain embodiments, the hydroxyl group-containing organicsubstrate is heteroaryl. In certain embodiments, the hydroxylgroup-containing organic substrate comprises a tautomer of a heteroarylhydroxyl group. In certain embodiments, the hydroxyl group-containingorganic substrate is heterocyclic. In certain embodiments, the hydroxylgroup-containing organic substrate comprises a tautomer of aheterocyclic hydroxyl group. In certain embodiments, the method furthercomprises a source of fluorine. In certain embodiments, the fluorinesource is a fluoride salt. In certain embodiments, the fluorine sourceis a sodium, potassium, or cesium fluoride salt. In certain embodiments,the fluorine source is the counter ion Q. In certain embodiments, themethod comprises approximately 1-10 equivalents of a fluorine source. Incertain embodiments, the method comprises approximately 1-5 equivalentsof a fluorine source. In certain embodiments, the method comprisesapproximately 5-10 equivalents of a fluorine source. In certainembodiments, the method comprises approximately 3-5 equivalents of afluorine source. In certain embodiments, the method comprises greaterthan 10 equivalents of a fluorine source. In certain embodiments, thefluorine source comprises ¹⁸F. In certain embodiments, the step ofcontacting is performed in the presence of an organic or inorganic base.In certain embodiments, the base is an inorganic base. In certainembodiments, the base is sodium, potassium, or cesium carbonate. Incertain embodiments, the method comprises approximately 1-10 equivalentsof a base. In certain embodiments, the method comprises approximately1-5 equivalents of a base. In certain embodiments, the method comprisesapproximately 5-10 equivalents of a base. In certain embodiments, themethod comprises approximately 3-5 equivalents of a base. In certainembodiments, the method comprises greater than 10 equivalents of a base.In certain embodiments, the step of contacting comprises heating thecompound of Formula (II) and a fluorine source. In certain embodiments,the compound of Formula (II) and the fluorine source are heated to atemperature of approximately 80-140° C. In certain embodiments, thecompound of Formula (II) and the fluorine source are heated to atemperature of approximately 100-120° C. In certain embodiments, thecompound of Formula (II) and the fluorine source are heated to atemperature of about 110° C. In certain embodiments, the step ofcontacting lasts 5 minutes or less. In certain embodiments, the step ofthe step of contacting lasts 15 minutes or less. In certain embodiments,the step of the step of contacting lasts 30 minutes or less. In certainembodiments, the step of the step of contacting lasts 1 hour or less. Incertain embodiments, the step of contacting lasts more than 1 hour. Incertain embodiments, the step of fluorinating a compound of Formula (II)or exchanging the anion Q is carried out in a mixture of water and anorganic solvent. In certain embodiments, the step of fluorinating acompound of Formula (II) or exchanging the anion Q is carried out in amixture of water and dioxane. In certain embodiments, the method furthercomprises purifying the fluorinated organic compound. In certainembodiments, said method is incorporated into an automated process bywhich PET imaging agents are produced via reaction of a compound ofFormula (II) and a source of ¹⁸F. In certain embodiments, the yield ofthe fluorinated organic compound from the organic compound is at leastabout 5%. In certain embodiments, the yield of the fluorinated organiccompound from the organic compound is at least about 10%. In certainembodiments, the yield of the fluorinated organic compound from theorganic compound is at least about 15%. In certain embodiments, theyield of the fluorinated organic compound from the organic compound isat least about 20%. In certain embodiments, the yield of the fluorinatedorganic compound from the organic compound is at least about 25%. Incertain embodiments, the yield of the fluorinated organic compound fromthe organic compound is at least about 30%. In certain embodiments, theyield of the fluorinated organic compound from the organic compound isat least about 35%. In certain embodiments, the yield of the fluorinatedorganic compound from the organic compound is at least about 40%. Incertain embodiments, the yield of the fluorinated organic compound fromthe organic compound is at least about 45%. In certain embodiments, theyield of the fluorinated organic compound from the organic compound isat least about 50%. In certain embodiments, the yield of the fluorinatedorganic compound from the organic compound is at least about 55%. Incertain embodiments, the yield of the fluorinated organic compound fromthe organic compound is at least about 60%. In certain embodiments, theyield of the fluorinated organic compound from the organic compound isat least about 65%. In certain embodiments, the yield of the fluorinatedorganic compound from the organic compound is at least about 70%. Incertain embodiments, the yield of the fluorinated organic compound fromthe organic compound is at least about 75%. In certain embodiments, theyield of the fluorinated organic compound from the organic compound isat least about 80%. In certain embodiments, the yield of the fluorinatedorganic compound from the organic compound is at least about 85%. Incertain embodiments, the yield of the fluorinated organic compound fromthe organic compound is at least about 90%. In certain embodiments, theyield of the fluorinated organic compound from the organic compound isat least about 95%. In certain embodiments, the yield of the fluorinatedorganic compound from the organic compound is greater than 95%.

In certain embodiments, the method further comprises exchanging an anionQ of a compound of Formula (II) with a fluoride or HF₂ anion. In certainembodiments, the ion exchange reaction is carried out using an anionexchange resin or anion exchange chromatography. In certain embodimentsthe anion exchange medium is a weak anion exchange resin. In certainembodiments, the anion exchange medium comprises primary, secondary, ortertiary amine functional groups. In certain embodiments, the anionexchange medium is Amberlite® CR5550, Amberlite® FPA51, Amberlite®FPA53, Amberlite® FPA54, Amberlite® FPA55, Amberlite® IRA-67, Amberlite®IRA-67RF, Amberlite® IRA-70RF, Amberlite® IRA-96, Amberlite® IRA-96RF,Amberlite® IRA-96SB, Amberlite® IRA743, Amberlyst® A21, Amberlyst® A23,Diaion® WA10, Diaion® WA30, Dowex® 66, Dowex® 66RF, Dowex® Marathon®WBA, Dowex® Marathon® WBA-2, Dowex® Monosphere® 66, Dowex® Monosphere®77, Dowex® WGR-2, Dowex® Upcore Mono WB-500, Duolite® A7, Duolite® A568,Lewatit® MonoPlus MP 64, Lewatit® MP-62, Lewatit® VP OC 1065, Toyopearl®DEAE-650M, or TSKgel®. In certain embodiments the anion exchange mediumis a strong anion exchange resin. In certain embodiments, the anionexchange medium comprises quaternary ammonium functional groups. Incertain embodiments, the anion exchange medium is Amberjet® 4200,Amberjet® 4600, Amberjet® 9000, Amberjet® 9800, Amberjet® UP4000,Amberlite® FPA40, Amberlite® FPA42, Amberlite® FPA90, Amberlite® FPA91,Amberlite® FPA98, Amberlite® IRA-400, Amberlite® IRA-402, Amberlite®IRA-405, Amberlite® IRA-410, Amberlite® IRA-458, Amberlite® IRA-458RF,Amberlite® IRA-478, Amberlite® IRA-743, Amberlite® IRA-900, Amberlite®IRA-900RF, Amberlite® IRA-910, Amberlite® IRA-958, Amberlite® IRN-78,Amberlite® IRN-9766, Amberlyst® A26, Ambersep® 400, Ambersep® 4400,Ambersep® 4550, Ambersep® 900, Ambersep® 920U, Ambersep® 920UHC,Ambersep® 920UXL, Ambersep® 940U, Diaion® HPA25, Dowex® 1X2, Dowex® 1X4,Dowex® 1X8, Dowex® 21K, Dowex® 22, Dowex® 2X8, Dowex® 550A, Dowex®Marathon®, Dowex® Marathon® A, Dowex® Marathon® A2, Dowex® Marathon® 11,Dowex® Marathon® MSA-1, Dowex® Marathon® MSA-2, Dowex® Monosphere® 550A,Dowex® Monosphere® 550A UPW, Dowex® RPU, Dowex® SBR-C, Dowex® UpcoreMono A2-500, Dowex® Upcore Mono A-500, Dowex® Upcore Mono A-625, Dowex®Upcore Mono MA-600, Dowex® XZ 91419, Imac® HP555, Lewatit® MonoPlus M500, Lewatit® MP-64, QAE Sephadex® A-50, QAE Sephadex® A-25, Toyopearl®QAE-550C, Toyopearl® SuperQ-650M, Chromafix®, or Chromabond® PS. Incertain embodiments, the anion exchange medium is apolystyrene-bicarbonate resin. In order to facilitate exchange of theanion Q, a solution of a compound of Formula (II) is passed over anionexchange medium or through a column containing anion exchange mediumwhich is infused with fluoride or HF₂ anions. In certain embodiments,between approximately 5 and 100 mg of anion exchange media is used. Incertain embodiments, between approximately 10 and 50 mg of anionexchange media is used. In certain embodiments, approximately 30 mg ofanion exchange media is used. In certain embodiments, betweenapproximately 2 and 20 micromoles of a compound of Formula (II) is used.In certain embodiments, between approximately 5 and 10 micromoles of acompound of Formula (II) is used. In certain embodiments, approximately8 micromoles of a compound of Formula (II) is used. In certainembodiments, the compound of Formula (II) is passed over anion exchangemedium or through a column containing anion exchange medium usingbetween 0.1 and 10 ml of solvent. In certain embodiments, the compoundof Formula (II) is passed over anion exchange medium or through a columncontaining anion exchange medium using between 0.2 and 1 ml of solvent.In certain embodiments, the compound of Formula (II) is passed overanion exchange medium or through a column containing anion exchangemedium using about 5 ml of solvent.

An another aspect, the present invention is directed to a method ofproducing a compound of Formula (I), the method comprising reacting acompound of Formula (I-e):

wherein

D is oxygen or sulfur;

R¹ and R² are independently selected from group consisting of C₁₋₆alkyl, C₆₋₁₀ aryl, C₆₋₁₀ aralkyl, 5-10 membered heteroaryl, 5-10membered heteroaralkyl, 4-10 membered heterocyclyl, 4-10 memberedheterocyclylalkyl, 3-10 membered carbocyclyl, and 3-10 memberedcarbocyclylalkyl, each of which is optionally substituted with 0 to 5occurrences of R⁵;

R³ and R⁴ are independently selected from the group consisting ofhydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, nitro, cyano, halo,C₁₋₆ haloalkyl, C₁₋₆ alkoxy, optionally substituted C₆₋₁₀ aryl,optionally substituted C₆₋₁₀ aralkyl, optionally substituted 5-10membered heteroaryl, optionally substituted 4-10 membered heterocyclyl,optionally substituted 3-10 membered carbocyclyl, optionally substituted4-10 membered heterocyclylalkyl, acyl, —NH₂, —NHR⁷, —N(R⁷)₂, —OH, —SH,—SO₂R⁷, —SOR⁷, —SO₂NR⁷ ₂, and —SR⁷;

R⁷ is independently selected from the group consisting of hydrogen,acyl, optionally substituted aliphatic, optionally substitutedcarbocyclyl, optionally substituted heterocyclyl, optionally substitutedaryl, and optionally substituted heteroaryl, or two R⁷ groups are takentogether with their intervening atoms to form an optionally substitutedheterocyclic ring;

R⁵ is independently selected from the group consisting of halo, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy,optionally substituted C₆₋₁₀ aryl, optionally substituted 5-10 memberedheteroaryl, optionally substituted 4-10 membered heterocyclyl,optionally substituted 3-10 membered carbocyclyl, nitro, cyano, acyl,—NH₂, —NHR⁷, —N(R⁷)₂, —OH, —SH, —SO₂R⁷, —SOR⁷, —SO₂NR⁷ ₂, and —SR⁷;

v is 0-3;

m is 1-5;

with a Brønsted acid, a Lewis acid, or an acid anhydride to produce thecompound of Formula (I).

In certain embodiments, R³ of compounds of Formula (I), (I-a), (I-b),(II), (II-a), (II-b), (III), (III-a), (III-b), (IV), (IV-a), (IV-b),(V), (V-a), (V-b), (VI), (VI-a), or (VI-b) is hydrogen. In certainembodiments, R⁴ of compounds of Formula (I), (I-a), (I-b), (II), (II-a),(II-b), (III), (III-a), (III-b), (IV), (IV-a), (IV-b), (V), (V-a),(V-b), (VI), (VI-a), or (VI-b) is hydrogen. In certain embodiments, bothR³ and R⁴ of compounds of Formula (I), (I-a), (I-b), (II), (II-a),(II-b), (III), (III-a), (III-b), (IV), (IV-a), (IV-b), (V), (V-a),(V-b), (VI), (VI-a), or (VI-b) are hydrogen.

In compounds of Formula (I), (I-a), (I-b), (II), (II-a), (II-b), (III),(III-a), (III-b), (IV), (IV-a), (IV-b), (V), (V-a), (V-b), (VI), (VI-a),or (VI-b), R³ and R⁴ are independently selected from the groupconsisting of hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, nitro,cyano, halo, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, optionally substituted C₆₋₁₀aryl, optionally substituted C₆₋₁₀ aralkyl, optionally substituted 5-10membered heteroaryl, optionally substituted 4-10 membered heterocyclyl,optionally substituted 3-10 membered carbocyclyl, optionally substituted4-10 membered heterocyclylalkyl, acyl, —NH₂, —NHR⁷, —N(R⁷)₂, —OH, —SH,—SO₂R⁷, —SOR⁷, —SO₂NR⁷ ₂, and —SR⁷. In certain embodiments, R³ ishydrogen. In certain embodiments, R³ is C₆ alkyl. In certainembodiments, R³ is C₂₋₆ alkenyl. In certain embodiments, R³ is C₂₋₆alkynyl. In certain embodiments, R³ is nitro. In certain embodiments, R³is cyano. In certain embodiments, R³ is halo. In certain embodiments, R³is C₁₋₆ haloalkyl. In certain embodiments, R³ is C₁₋₆ alkoxy. In certainembodiments, R³ is optionally substituted C₆₋₁₀ aryl. In certainembodiments, R³ is optionally substituted C₆₋₁₀ aralkyl. In certainembodiments, R³ is optionally substituted 5-10 membered heteroaryl. Incertain embodiments, R³ is optionally substituted 4-10 memberedheterocyclyl. In certain embodiments, R³ is optionally substituted 3-10membered carbocyclyl. In certain embodiments, R³ is optionallysubstituted 4-10 membered heterocyclylalkyl. In certain embodiments, R³is acyl. In certain embodiments, R³ is —NH₂. In certain embodiments, R³is —NHR⁷. In certain embodiments, R³ is —N(R⁷)₂. In certain embodiments,R³ is —OH. In certain embodiments, R³ is —SH. In certain embodiments, R³is —SO₂R⁷. In certain embodiments, R³ is —SOR⁷. In certain embodiments,R³ is —SO₂NR⁷ ₂. In certain embodiments, R³ is —SR⁷. In certainembodiments, R⁴ is hydrogen. In certain embodiments, R⁴ is C₁₋₆ alkyl.In certain embodiments, R⁴ is C₂₋₆ alkenyl. In certain embodiments, R⁴is C₂₋₆ alkynyl. In certain embodiments, R⁴ is nitro. In certainembodiments, R⁴ is cyano. In certain embodiments, R⁴ is halo. In certainembodiments, R⁴ is C₁₋₆ haloalkyl. In certain embodiments, R⁴ is C₁₋₆alkoxy. In certain embodiments, R⁴ is optionally substituted C₆₋₁₀ aryl.In certain embodiments, R⁴ is optionally substituted C₆₋₁₀ aralkyl. Incertain embodiments, R⁴ is optionally substituted 5-10 memberedheteroaryl. In certain embodiments, R⁴ is optionally substituted 4-10membered heterocyclyl. In certain embodiments, R⁴ is optionallysubstituted 3-10 membered carbocyclyl. In certain embodiments, R⁴ isoptionally substituted 4-10 membered heterocyclylalkyl. In certainembodiments, R⁴ is acyl. In certain embodiments, R⁴ is —NH₂. In certainembodiments, R⁴ is —NHR⁷. In certain embodiments, R⁴ is —N(R⁷)₂. Incertain embodiments, R⁴ is —OH. In certain embodiments, R⁴ is —SH. Incertain embodiments, R⁴ is —SO₂R⁷. In certain embodiments, R⁴ is —SOR⁷.In certain embodiments, R⁴ is —SO₂NR⁷ ₂. In certain embodiments, R⁴ is—SR⁷.

In compounds of Formula (I), (I-a), (II), (II-a), (III), (III-a), (IV),(IV-a), (V), (V-a), (VI), or (VI-a), R⁵ is independently selected fromthe group consisting of halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₆ haloalkyl, C₁₋₆ alkoxy, optionally substituted C₆₋₁₀ aryl,optionally substituted 5-10 membered heteroaryl, optionally substituted4-10 membered heterocyclyl, optionally substituted 3-10 memberedcarbocyclyl, nitro, cyano, acyl, —NH₂, —NHR⁷, —N(R⁷)₂, —OH, —SH, —SO₂R⁷,—SOR⁷, —SO₂NR⁷ ₂, and —SR⁷. In certain embodiments, R⁵ is halo. Incertain embodiments, R⁵ is C₁₋₆ alkyl. In certain embodiments, R⁵ isC₂₋₆ alkenyl. In certain embodiments, R⁵ is C₂₋₆ alkynyl. In certainembodiments, R⁵ is C₁₋₆ haloalkyl. In certain embodiments, R⁵ is C₁₋₆alkoxy. In certain embodiments, R⁵ is optionally substituted C₆₋₁₀ aryl.In certain embodiments, R⁵ is optionally substituted 5-10 memberedheteroaryl. In certain embodiments, R⁵ is optionally substituted 4-10membered heterocyclyl. In certain embodiments, R⁵ is optionallysubstituted 3-10 membered carbocyclyl. In certain embodiments, R⁵ isnitro. In certain embodiments, R⁵ is cyano. In certain embodiments, R⁵is acyl. In certain embodiments, R⁵ is —NH₂. In certain embodiments, R⁵is —NHR⁷. In certain embodiments, R⁵ is —OH. In certain embodiments, R⁵is —SH. In certain embodiments, R⁵ is —SO₂R⁷. In certain embodiments, R⁵is —SOR⁷. In certain embodiments, R⁵ is —SO₂NR⁷ ₂. In certainembodiments, R⁵ is —SR⁷.

In compounds of Formula (I), (I-a), (I-b), (II), (II-a), (II-b), (III),(III-a), (III-b), (IV), (IV-a), (IV-b), (V), (V-a), (V-b), (VI), (VI-a),or (VI-b), R⁷ is independently selected from the group consisting ofhydrogen, acyl, optionally substituted aliphatic, optionally substitutedcarbocyclyl, optionally substituted heterocyclyl, optionally substitutedaryl, and optionally substituted heteroaryl, or two R⁷ groups are takentogether with their intervening atoms to form an optionally substitutedheterocyclic ring. In certain embodiments, R⁷ is hydrogen. In certainembodiments, R⁷ is optionally substituted aliphatic. In certainembodiments, R⁷ is optionally substituted carbocyclyl. In certainembodiments, R⁷ is optionally substituted heterocyclyl. In certainembodiments, R⁷ is optionally substituted aryl. In certain embodiments,R⁷ is optionally substituted heteroaryl. In certain embodiments, two R⁷groups are taken together with their intervening atoms to form anoptionally substituted heterocyclic ring.

In compounds of Formula (II-f), (VI), (VI-a), (VI-b), (VI-c), (VI-d),(VI-e), or (VI-f), each occurrence of R⁸ is independently selected fromthe group consisting of C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, nitro,cyano, halo, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, optionally substituted C₆₋₁₀aryl, optionally substituted C₆₋₁₀ aralkyl, optionally substituted 5-10membered heteroaryl, optionally substituted 4-10 membered heterocyclyl,optionally substituted 3-10 membered carbocyclyl, optionally substituted4-10 membered heterocyclylalkyl, acyl, —N(R^(8a))₂, —OR^(8a),—CO₂R^(8a), —SO₂R^(8a), —SOR^(8a), —SO₂N(R^(8a))₂, and —SR^(8a). Incertain embodiments, R⁸ is C₁₋₆ alkyl. In certain embodiments, R⁸ isC₂₋₆ alkenyl. In certain embodiments, R⁸ is C₂₋₆ alkynyl. In certainembodiments, R⁸ is nitro. In certain embodiments, R⁸ is cyano. Incertain embodiments, R⁸ is halo. In certain embodiments, R⁸ is C₁₋₆haloalkyl. In certain embodiments, R⁸ is C₁₋₆ alkoxy. In certainembodiments, R⁸ is optionally substituted C₆₋₁₀ aryl. In certainembodiments, R⁸ is optionally substituted C₆₋₁₀ aralkyl. In certainembodiments, R⁸ is optionally substituted 5-10 membered heteroaryl. Incertain embodiments, R⁸ is optionally substituted 4-10 memberedheterocyclyl. In certain embodiments, R⁸ is optionally substituted 3-10membered carbocyclyl. In certain embodiments, R⁸ is optionallysubstituted 4-10 membered heterocyclylalkyl. In certain embodiments, R⁸is acyl. In certain embodiments, R⁸ is —N(R^(8a))₂. In certainembodiments, R⁸ is —NH₂. In certain embodiments, R⁸ is —OR^(8a). Incertain embodiments, R⁸ is —OH. In certain embodiments, R⁸ is—CO₂R^(8a). In certain embodiments, R⁸ is —CO₂H. In certain embodiments,R⁸ is —SO₂R^(8a). In certain embodiments, R⁸ is —SO₂H. In certainembodiments, R⁸ is —SOR^(8a). In certain embodiments, R⁸ is —SOH. Incertain embodiments, R⁸ is —SO₂N(R^(8a))₂. In certain embodiments, R⁸ is—SO₂NH₂. In certain embodiments, R⁸ is —SR^(8a). In certain embodiments,R⁸ is —SH.

In compounds of Formula (II-f), (VI), (VI-a), (VI-b), (VI-c), (VI-d),(VI-e), or (VI-f), each occurrence of R⁹ is independently selected fromthe group consisting of C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, nitro,cyano, halo, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, optionally substituted C₆₋₁₀aryl, optionally substituted C₆₋₁₀ aralkyl, optionally substituted 5-10membered heteroaryl, optionally substituted 4-10 membered heterocyclyl,optionally substituted 3-10 membered carbocyclyl, optionally substituted4-10 membered heterocyclylalkyl, acyl, —N(R^(9a))₂, —OR^(9a),—CO₂R^(9a), —SO₂R^(9a), —SOR^(9a), —SO₂N(R^(9a))₂, and —SR^(9a). Incertain embodiments, R⁹ is C₁₋₆ alkyl. In certain embodiments, R⁹ isC₂₋₆ alkenyl. In certain embodiments, R⁹ is C₂₋₆ alkynyl. In certainembodiments, R⁹ is nitro. In certain embodiments, R⁹ is cyano. Incertain embodiments, R⁹ is halo. In certain embodiments, R⁹ is C₁₋₆haloalkyl. In certain embodiments, R⁹ is C₁₋₆ alkoxy. In certainembodiments, R⁹ is optionally substituted C₆₋₁₀ aryl. In certainembodiments, R⁹ is optionally substituted C₆₋₁₀ aralkyl. In certainembodiments, R⁹ is optionally substituted 5-10 membered heteroaryl. Incertain embodiments, R⁹ is optionally substituted 4-10 memberedheterocyclyl. In certain embodiments, R⁹ is optionally substituted 3-10membered carbocyclyl. In certain embodiments, R⁹ is optionallysubstituted 4-10 membered heterocyclylalkyl. In certain embodiments, R⁹is acyl. In certain embodiments, R⁹ is —N(R^(9a))₂. In certainembodiments, R⁹ is —NH₂. In certain embodiments, R⁹ is —OR^(9a). Incertain embodiments, R⁹ is —OH. In certain embodiments, R⁹ is—CO₂R^(9a). In certain embodiments, R⁹ is —CO₂H. In certain embodiments,R⁹ is —SO₂R^(9a). In certain embodiments, R⁹ is —SO₂H. In certainembodiments, R⁹ is —SOR^(9a) In certain embodiments, R⁹ is —SOH. Incertain embodiments, R⁹ is —SO₂N(R^(9a))₂. In certain embodiments, R⁹ is—SO₂NH₂. In certain embodiments, R⁹ is —SR^(9a). In certain embodiments,R⁹ is —SH.

In compounds of Formula (II-f), (VI), (VI-a), (VI-b), (VI-c), (VI-d),(VI-e), or (VI-f), p is 0, 1, 2, or 3. In certain embodiments, p is 0.In certain embodiments, p is 1. In certain embodiments, p is 2. Incertain embodiments, p is 3.

In methods involving structures of Formula (I), (I-e), (II), or (VI), R³and R⁴ are independently selected from the group consisting of hydrogen,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, nitro, cyano, halo, C₁₋₆haloalkyl, C₁₋₆ alkoxy, optionally substituted C₆₋₁₀ aryl, optionallysubstituted C₆₋₁₀ aralkyl, optionally substituted 5-10 memberedheteroaryl, optionally substituted 4-10 membered heterocyclyl,optionally substituted 3-10 membered carbocyclyl, optionally substituted4-10 membered heterocyclylalkyl, acyl, —NH₂, —NHR⁷, —N(R⁷)₂, —OH, —SH,—SO₂R⁷, —SOR⁷, —SO₂NR⁷ ₂, and —SR⁷. In certain embodiments, R³ ishydrogen. In certain embodiments, R³ is C₁₋₆ alkyl. In certainembodiments, R³ is C₂₋₆ alkenyl. In certain embodiments, R³ is C₂₋₆alkynyl. In certain embodiments, R³ is nitro. In certain embodiments, R³is cyano. In certain embodiments, R³ is halo. In certain embodiments, R³is C₁₋₆ haloalkyl. In certain embodiments, R³ is C₁₋₆ alkoxy. In certainembodiments, R³ is optionally substituted C₆₋₁₀ aryl. In certainembodiments, R³ is optionally substituted C₆₋₁₀ aralkyl. In certainembodiments, R³ is optionally substituted 5-10 membered heteroaryl. Incertain embodiments, R³ is optionally substituted 4-10 memberedheterocyclyl. In certain embodiments, R³ is optionally substituted 3-10membered carbocyclyl. In certain embodiments, R³ is optionallysubstituted 4-10 membered heterocyclylalkyl. In certain embodiments, R³is acyl. In certain embodiments, R³ is —NH₂. In certain embodiments, R³is —NHR⁷. In certain embodiments, R³ is —N(R⁷)₂. In certain embodiments,R³ is —OH. In certain embodiments, R³ is —SH. In certain embodiments, R³is —SO₂R⁷. In certain embodiments, R³ is —SOR⁷. In certain embodiments,R³ is —SO₂NR⁷ ₂. In certain embodiments, R³ is —SR⁷. In certainembodiments, R⁴ is hydrogen. In certain embodiments, R⁴ is C₁₋₆ alkyl.In certain embodiments, R⁴ is C₂₋₆ alkenyl. In certain embodiments, R⁴is C₂₋₆ alkynyl. In certain embodiments, R⁴ is nitro. In certainembodiments, R⁴ is cyano. In certain embodiments, R⁴ is halo. In certainembodiments, R⁴ is C₁₋₆ haloalkyl. In certain embodiments, R⁴ is C₁₋₆alkoxy. In certain embodiments, R⁴ is optionally substituted C₆₋₁₀ aryl.In certain embodiments, R⁴ is optionally substituted C₆₋₁₀ aralkyl. Incertain embodiments, R⁴ is optionally substituted 5-10 memberedheteroaryl. In certain embodiments, R⁴ is optionally substituted 4-10membered heterocyclyl. In certain embodiments, R⁴ is optionallysubstituted 3-10 membered carbocyclyl. In certain embodiments, R⁴ isoptionally substituted 4-10 membered heterocyclylalkyl. In certainembodiments, R⁴ is acyl. In certain embodiments, R⁴ is —NH₂. In certainembodiments, R⁴ is —NHR⁷. In certain embodiments, R⁴ is —N(R⁷)₂. Incertain embodiments, R⁴ is —OH. In certain embodiments, R⁴ is —SH. Incertain embodiments, R⁴ is —SO₂R⁷. In certain embodiments, R⁴ is —SOR⁷.In certain embodiments, R⁴ is —SO₂NR⁷ ₂. In certain embodiments, R⁴ is—SR⁷.

In methods involving structures of Formula (I), (I-e), (II), or (VI), R⁵is independently selected from the group consisting of halo, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, optionallysubstituted C₆₋₁₀ aryl, optionally substituted 5-10 membered heteroaryl,optionally substituted 4-10 membered heterocyclyl, optionallysubstituted 3-10 membered carbocyclyl, nitro, cyano, acyl, —NH₂, —NHR⁷,—N(R⁷)₂, —OH, —SH, —SO₂R⁷, —SOR⁷, —SO₂NR⁷ ₂, and —SR⁷. In certainembodiments, R⁵ is halo. In certain embodiments, R⁵ is C₁₋₆ alkyl. Incertain embodiments, R⁵ is C₂₋₆ alkenyl. In certain embodiments, R⁵ isC₂₋₆ alkynyl. In certain embodiments, R⁵ is C₁₋₆ haloalkyl. In certainembodiments, R⁵ is C₁₋₆ alkoxy. In certain embodiments, R⁵ is optionallysubstituted C₆₋₁₀ aryl. In certain embodiments, R⁵ is optionallysubstituted 5-10 membered heteroaryl. In certain embodiments, R⁵ isoptionally substituted 4-10 membered heterocyclyl. In certainembodiments, R⁵ is optionally substituted 3-10 membered carbocyclyl. Incertain embodiments, R⁵ is nitro. In certain embodiments, R⁵ is cyano.In certain embodiments, R⁵ is acyl. In certain embodiments, R⁵ is —NH₂.In certain embodiments, R⁵ is —NHR⁷. In certain embodiments, R⁵ is —OH.In certain embodiments, R⁵ is —SH. In certain embodiments, R⁵ is —SO₂R⁷.In certain embodiments, R⁵ is —SOR⁷. In certain embodiments, R⁵ is—SO₂NR⁷ ₂. In certain embodiments, R⁵ is —SR⁷.

In methods involving structures of Formula (I), (I-e), (II), or (VI), R⁷is independently selected from the group consisting of hydrogen, acyl,optionally substituted aliphatic, optionally substituted carbocyclyl,optionally substituted heterocyclyl, optionally substituted aryl, andoptionally substituted heteroaryl, or two R⁷ groups are taken togetherwith their intervening atoms to form an optionally substitutedheterocyclic ring. In certain embodiments, R⁷ is hydrogen. In certainembodiments, R⁷ is optionally substituted aliphatic. In certainembodiments, R⁷ is optionally substituted carbocyclyl. In certainembodiments, R⁷ is optionally substituted heterocyclyl. In certainembodiments, R⁷ is optionally substituted aryl. In certain embodiments,R⁷ is optionally substituted heteroaryl. In certain embodiments, two R⁷groups are taken together with their intervening atoms to form anoptionally substituted heterocyclic ring.

In methods involving a compound of Formula (VI), each occurrence of R⁸is independently selected from the group consisting of C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, nitro, cyano, halo, C₁₋₆ haloalkyl, C₁₋₆ alkoxy,optionally substituted C₆₋₁₀ aryl, optionally substituted C₆₋₁₀ aralkyl,optionally substituted 5-10 membered heteroaryl, optionally substituted4-10 membered heterocyclyl, optionally substituted 3-10 memberedcarbocyclyl, optionally substituted 4-10 membered heterocyclylalkyl,acyl, —N(R^(8a))₂, —OR^(8a), —CO₂R^(8a), —SO₂R^(8a), —SOR^(8a),—SO₂N(R^(8a))₂, and —SR^(8a). In certain embodiments, R⁸ is C₁₋₆ alkyl.In certain embodiments, R⁸ is C₂₋₆ alkenyl. In certain embodiments, R⁸is C₂₋₆ alkynyl. In certain embodiments, R⁸ is nitro. In certainembodiments, R⁸ is cyano. In certain embodiments, R⁸ is halo. In certainembodiments, R⁸ is C₁₋₆ haloalkyl. In certain embodiments, R⁸ is C₁₋₆alkoxy. In certain embodiments, R⁸ is optionally substituted C₆₋₁₀ aryl.In certain embodiments, R⁸ is optionally substituted C₆₋₁₀ aralkyl. Incertain embodiments, R⁸ is optionally substituted 5-10 memberedheteroaryl. In certain embodiments, R⁸ is optionally substituted 4-10membered heterocyclyl. In certain embodiments, R⁸ is optionallysubstituted 3-10 membered carbocyclyl. In certain embodiments, R⁸ isoptionally substituted 4-10 membered heterocyclylalkyl. In certainembodiments, R⁸ is acyl. In certain embodiments, R⁸ is —N(R^(8a))₂. Incertain embodiments, R⁸ is —NH₂. In certain embodiments, R⁸ is —OR^(8a).In certain embodiments, R⁸ is —OH. In certain embodiments, R⁸ is—CO₂R^(8a). In certain embodiments, R⁸ is —CO₂H. In certain embodiments,R⁸ is —SO₂R^(8a). In certain embodiments, R⁸ is —SO₂H. In certainembodiments, R⁸ is —SOR^(8a). In certain embodiments, R⁸ is —SOH. Incertain embodiments, R⁸ is —SO₂N(R^(8a))₂. In certain embodiments, R⁸ is—SO₂NH₂. In certain embodiments, R⁸ is —SR^(8a). In certain embodiments,R⁸ is —SH.

In methods involving a compound of Formula (VI), each occurrence of R⁹is independently selected from the group consisting of C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, nitro, cyano, halo, C₁₋₆ haloalkyl, C₁₋₆ alkoxy,optionally substituted C₆₋₁₀ aryl, optionally substituted C₆₋₁₀ aralkyl,optionally substituted 5-10 membered heteroaryl, optionally substituted4-10 membered heterocyclyl, optionally substituted 3-10 memberedcarbocyclyl, optionally substituted 4-10 membered heterocyclylalkyl,acyl, —N(R^(9a))₂, —OR^(9a), —CO₂R^(9a), —SO₂R^(9a), —SOR^(9a),—SO₂N(R^(9a))₂, and —SR^(9a). In certain embodiments, R⁹ is C₁₋₆ alkyl.In certain embodiments, R⁹ is C₂₋₆ alkenyl. In certain embodiments, R⁹is C₂₋₆ alkynyl. In certain embodiments, R⁹ is nitro. In certainembodiments, R⁹ is cyano. In certain embodiments, R⁹ is halo. In certainembodiments, R⁹ is C₁₋₆ haloalkyl. In certain embodiments, R⁹ is C₁₋₆alkoxy. In certain embodiments, R⁹ is optionally substituted C₆₋₁₀ aryl.In certain embodiments, R⁹ is optionally substituted C₆₋₁₀ aralkyl. Incertain embodiments, R⁹ is optionally substituted 5-10 memberedheteroaryl. In certain embodiments, R⁹ is optionally substituted 4-10membered heterocyclyl. In certain embodiments, R⁹ is optionallysubstituted 3-10 membered carbocyclyl. In certain embodiments, R⁹ isoptionally substituted 4-10 membered heterocyclylalkyl. In certainembodiments, R⁹ is acyl. In certain embodiments, R⁹ is —N(R^(9a))₂. Incertain embodiments, R⁹ is —NH₂. In certain embodiments, R⁹ is —OR^(9a).In certain embodiments, R⁹ is —OH. In certain embodiments, R⁹ is—CO₂R^(9a). In certain embodiments, R⁹ is —CO₂H. In certain embodiments,R⁹ is —SO₂R^(9a). In certain embodiments, R⁹ is —SO₂H. In certainembodiments, R⁹ is —SOR^(9a). In certain embodiments, R⁹ is —SOH. Incertain embodiments, R⁹ is —SO₂N(R^(9a))₂. In certain embodiments, R⁹ is—SO₂NH₂. In certain embodiments, R⁹ is —SR^(9a). In certain embodiments,R⁹ is —SH.

In methods involving a compound of Formula (VI), p is 0, 1, 2, or 3. Incertain embodiments, p is 0. In certain embodiments, p is 1. In certainembodiments, p is 2. In certain embodiments, p is 3.

In certain embodiments, the method further comprises reacting thecompound of Formula (I) or Formula (VI) with a hydroxyl group-containingorganic substrate or a tautomer thereof under conditions sufficient tofluorinate the organic compound, thereby providing a fluorinated organiccompound. In certain embodiments, the fluorinated organic compoundcomprises ¹⁸F or ¹⁹F.

In another aspect, the present invention is directed to a reactionmixture comprising a compound of Formula (I), (II), (III), (IV), (V), or(VI) and a fluorine source. In certain embodiments, the reaction mixturecomprises a compound of Formula (I-e), an acid, a base, an organiccompound and a fluorine source.

In another aspect, the present invention is directed to a kit comprisinga compound of Formula (I), (II), (III), (IV), (V), (VI), or (I-e) and acontainer. In certain embodiments, the kit further comprisesinstructions for use of the compound of Formula (I), (II), (III), (IV),(V), (VI), or (I-e). In certain embodiments, the kit further comprises abase and a fluorine source.

Organic Compounds

Compounds (e.g., a compound of Formula (I), (II), or (VI)) useful in amethod of fluorinating a hydroxyl group-containing organic compound orsubstrate or tautomer thereof are described herein. A hydroxylgroup-containing organic compound or substrate or tautomer thereof isrepresented herein as

Following reaction with the hydroxyl group, the hydroxylgroup-containing organic compound or substrate or tautomer thereof isrepresented herein as

An organic compound or substrate is an organic molecule of any molecularweight. In certain embodiments, the molecule is a small organicmolecule. In certain embodiments, the small organic molecule includesany molecule having a molecular weight of less than 2000 g/mol. Incertain embodiments, the small organic molecule includes any moleculehaving a molecular weight of less than 1900 g/mol. In certainembodiments, the small organic molecule includes any molecule having amolecular weight of less than 1800 g/mol. In certain embodiments, thesmall organic molecule includes any molecule having a molecular weightof less than 1700 g/mol. In certain embodiments, the small organicmolecule includes any molecule having a molecular weight of less than1600 g/mol. In certain embodiments, the small organic molecule includesany molecule having a molecular weight of less than 1500 g/mol. Incertain embodiments, the small organic molecule includes any moleculehaving a molecular weight of less than 1400 g/mol. In certainembodiments, the small organic molecule includes any molecule having amolecular weight of less than 1300 g/mol. In certain embodiments, thesmall organic molecule includes any molecule having a molecular weightof less than 1200 g/mol. In certain embodiments, the small organicmolecule includes any molecule having a molecular weight of less than1100 g/mol. In certain embodiments, the small organic molecule includesany molecule having a molecular weight of less than 1000 g/mol. Incertain embodiments, the small organic molecule includes any moleculehaving a molecular weight of less than 900 g/mol. In certainembodiments, the small organic molecule includes any molecule having amolecular weight of less than 800 g/mol. In certain embodiments, thesmall organic molecule includes any molecule having a molecular weightof less than 700 g/mol. In certain embodiments, the small organicmolecule includes any molecule having a molecular weight of less than600 g/mol. In certain embodiments, the small organic molecule includesany molecule having a molecular weight of less than 500 g/mol. Incertain embodiments, the small organic molecule includes any moleculehaving a molecular weight of less than 400 g/mol. In certainembodiments, the small organic molecule includes any molecule having amolecular weight of less than 300 g/mol. In certain embodiments, thesmall organic molecule includes any molecule having a molecular weightof less than 200 g/mol. In certain embodiments, the small organicmolecule includes any molecule having a molecular weight of less than100 g/mol. In certain embodiments, the molecule is a large organicmolecule. In certain embodiments, the large organic molecule is between1000 g/mol to 5000 g/mol. In certain embodiments, the large organicmolecule is between 1000 g/mol to 3000 g/mol. In certain embodiments,the large organic molecule is between 1000 g/mol to 2000 g/mol. Incertain embodiments, the large organic molecule is between 1000 g/mol to1500 g/mol. Organic compounds include aliphatic, alkyl, alkenyl,carbocyclic, aryl, heteroaryl and heterocyclyl containing compoundscontaining a wide variety of substitutents. In certain embodiments, thehydroxyl-group containing organic compound is(S)-2-amino-3-(3,4-dihydroxyphenyl)propanoic acid (L-DOPA),(R)-2-amino-3-(3,4-dihydroxyphenyl)propanoic acid (D-DOPA), or a mixturethereof. In certain embodiments, the hydroxyl-group containing organiccompound is a protected L-DOPA, D-DOPA, or a mixture thereof. In certainembodiments, the hydroxyl-group containing organic compound is L-DOPA,D-DOPA, or a mixture thereof wherein one of the hydroxyl groups areprotected with an oxygen protecting group. In certain embodiments, thehydroxyl-group containing organic compound is L-DOPA, D-DOPA, or amixture thereof wherein both of the hydroxyl groups are protected withan oxygen protecting group. In certain embodiments, the hydroxyl-groupcontaining organic compound is L-DOPA, D-DOPA, or a mixture thereofwherein the amine group is protected with a nitrogen protecting group.

In certain embodiments, the organic compound contains a chiral center.In certain embodiments, the organic compound is further substituted withone or more functional groups (e.g., alcohols, aldehydes, ketones,esters, alkenes, alkoxy groups, cyano groups, amines, amides, andN-oxides). In certain embodiments, the functional groups areunprotected. In certain embodiments, the organic compound is a precursorof a pharmaceutical agent.

Fluorine or Fluoride Sources

The methods described herein generally involve a fluorine source. Theterms “fluorine source” and “fluoride source” are used interchangeablyherein. In certain embodiments, the fluorine source is a nucleophilicfluorine source (e.g., a fluoride, F). In certain embodiments, thefluorine source is commercially available. In certain embodiments, thefluorine source is also an inorganic fluorine source. Exemplary fluorinesources include sodium fluoride (NaF), cesium fluoride (CsF), potassiumfluoride (KF), ammonium fluoride (NH₄F), calcium fluoride (CaF₂),lithium fluoride (LiF), aluminum fluoride (AlF₃), barium fluoride(BaF₂), silver fluoride (AgF and AgF₂), tetramethylammonium fluoride(Me₄NF), magnesium fluoride (MgF₂), zinc fluoride (ZnF₂), copperfluoride (CuF and CuF₂), TBAF (^(n)Bu₄NF), cerium fluoride (CeF₃), tinfluoride (SnF₂), scandium fluoride (ScF₃), and indium fluoride (InF₃).In certain embodiments, the fluorine source is the counter ion Q.

The fluorine source may be enriched with a particular isotope offluorine. In certain embodiments, the fluorine source is labeled with¹⁹F. In certain embodiments, use of a ¹⁹F-labeled fluorine source in theinventive method provides a fluorinated ¹⁹F-labeled organic compound.

In certain embodiments, the fluorine source is labeled with ¹⁸F (i.e.,provides a ¹⁸F fluorine to the reaction mixture). In certainembodiments, use of a ¹⁸F-labeled fluorine source in the inventivemethod provides a fluorinated ¹⁸F-labeled organic compound.

However, in certain embodiments, the fluorine source is labeled with amixture of ¹⁸F and ¹⁹F. In certain embodiments, use of a mixture of ¹⁹Fand ¹⁸F fluorine sources in the inventive method provides a mixture offluorinated ¹⁹F-labeled organic compound and fluorinated ¹⁸F-labeledorganic compound.

Reaction Conditions

Described herein are methods of producing a fluorinating reagent andmethods of fluorinating hydroxyl group-containing organic compounds(e.g., a phenol, hydroxypyridine, etc.) or tautomers thereof (e.g.,pyridone) using a fluorinating agent (e.g., a compound of Formula (I)).In certain embodiments, the reaction further comprises a solvent.Exemplary solvents include non-polar solvents (e.g., toluene, dioxane,or benzene). In certain embodiments, the reaction is performed underambient temperature, pressure and atmosphere. In certain embodiments,the reaction is performed in an inert atmosphere (e.g., an atmospherethat is substantially free of dioxygen or water). In certainembodiments, the reaction is performed under anhydrous conditions (e.g.,in a solvent that is substantially free of water). In certainembodiments, the reaction is heated. In certain embodiments, thereaction is heated to about 110° C. In certain embodiments, the reactionis cooled. In certain embodiments, the reaction is performed at roomtemperature (e.g., about 20-25° C.).

In certain embodiments, the reaction proceeds in a single step. In aone-step procedure, an organic compound comprising a substrate and afluorine source, and optionally an additional reagent such as a base(e.g., NaOH, KOH, BaO, MgO, NaHCO₃, KHCO₃, Na₂CO₃, Ba(OH)₂,2,6-lutidine, or K₂CO₃) or a salt (e.g., cesium fluoride), to yield afluorinated organic compound.

In certain embodiments, the reaction proceeds in two steps. In atwo-step procedure, the organic compound comprising substrate may befirst reacted with a compound of Formula (I) in the presence of anoptional additional reagent, such as a base (e.g., NaOH, KOH, BaO, MgO,NaHCO₃, KHCO₃, Na₂CO₃, Ba(OH)₂, 2,6-lutidine, or K₂CO₃). In certainembodiments, an intermediate product of Formula (II), Formula (III),Formula (IV), or Formula (V) is isolated from the first reaction. Theintermediate product may be further reacted with a fluorinating agent inthe second step. In these embodiments, isolation enables theinvestigator to evaluate numerous reaction conditions for subsequentfluorination. In certain embodiments, each step further comprises asolvent, and the solvents may be the same or may be different. Forexample, the first step may take place in acetonitrile, while the secondstep may take place in acetone. In certain embodiments, each step isperformed at a different temperature. For example, the first step mayinvolve cooling (e.g., the reaction mixture at 0° C.), while the secondstep may be performed at ambient temperature.

In certain embodiments, a compound of the present invention, a compoundof the methods described herein, or the hydroxyl group-containingorganic molecule is immobilized on a solid support. In certainembodiments, a compound of Formula (I) is immobilized on a solidsupport. In certain embodiments, a compound of Formula (I-a) isimmobilized on a solid support. In certain embodiments, a compound ofFormula (I-b) is immobilized on a solid support. In certain embodiments,a compound of Formula (I-c) is immobilized on a solid support. Incertain embodiments, a compound of Formula (I-d) is immobilized on asolid support. In certain embodiments, a compound of Formula (I-e) isimmobilized on a solid support. In certain embodiments, a compound ofFormula (II) is immobilized on a solid support. In certain embodiments,a compound of Formula (II-a) is immobilized on a solid support. Incertain embodiments, a compound of Formula (II-b) is immobilized on asolid support. In certain embodiments, a compound of Formula (II-c) isimmobilized on a solid support. In certain embodiments, a compound ofFormula (II-d) is immobilized on a solid support. In certainembodiments, a compound of Formula (II-e) is immobilized on a solidsupport. In certain embodiments, a compound of Formula (II-f) isimmobilized on a solid support. In certain embodiments, a compound ofFormula (III) is immobilized on a solid support. In certain embodiments,a compound of Formula (III-a) is immobilized on a solid support. Incertain embodiments, a compound of Formula (III-b) is immobilized on asolid support. In certain embodiments, a compound of Formula (III-c) isimmobilized on a solid support. In certain embodiments, a compound ofFormula (IV) is immobilized on a solid support. In certain embodiments,a compound of Formula (IV-a) is immobilized on a solid support. Incertain embodiments, a compound of Formula (IV-b) is immobilized on asolid support. In certain embodiments, a compound of Formula (IV-c) isimmobilized on a solid support. In certain embodiments, a compound ofFormula (V) is immobilized on a solid support. In certain embodiments, acompound of Formula (V-a) is immobilized on a solid support. In certainembodiments, a compound of Formula (V-b) is immobilized on a solidsupport. In certain embodiments, a compound of Formula (V-c) isimmobilized on a solid support. In certain embodiments, a compound ofFormula (VI) is immobilized on a solid support. In certain embodiments,a compound of Formula (VI-a) is immobilized on a solid support. Incertain embodiments, a compound of Formula (VI-b) is immobilized on asolid support. In certain embodiments, a compound of Formula (VI-c) isimmobilized on a solid support. In certain embodiments, a compound ofFormula (VI-d) is immobilized on a solid support. In certainembodiments, a compound of Formula (VI-e) is immobilized on a solidsupport. In certain embodiments, a compound of Formula (VI-f) isimmobilized on a solid support.

In certain embodiments, the fluorination takes place at a late stage inthe synthesis of a fluorinated organic compound. In certain embodiments,the fluorination is the last step in the synthesis of the fluorinatedorganic compound. In certain embodiments, fluorination at the last stepin the synthesis of the fluorinated organic compound comprisespreparation of a PET probe.

In certain embodiments, subsequent to the reaction, the fluorinatedorganic compound is purified from the reaction mixture. In certainembodiments, the fluorinated organic compound is purified by columnchromatography on silica gel. In certain embodiments, the fluorinatedorganic compound is purified by preparative thin-layer chromatography.In certain embodiments, the fluorinated organic compound is purified byreverse or normal phase HPLC. Methods of purification via thesetechniques are described in Snyder, Introduction to Modern LiquidChromatography (John Wiley & Sons, NJ, 2010) and McMaster, HPLC: APractical User's Guide (John Wiley & Sons, NJ, 2007).

Reaction Products

Described herein are methods of making fluorinated organic compounds. Incertain embodiments, the fluorinated organic compounds are generatedfrom their corresponding precursors in yields of at least about 5%, 10%,15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%,85%, 90%, 95%, 97%, 98%, 99%, or 100%.

In certain embodiments, described herein are methods of fluorinatingorganic compounds with ¹⁸F. In certain embodiments, the ¹⁸F-labeledorganic compounds are generated from their corresponding precursors inradiochemical yields of at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%,40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 97%, 98%,99%, or 100%.

The reaction conditions described herein are tolerant of many functionalgroups as well as chiral centers. In certain embodiments, thefluorinated organic compound is further substituted by one or morefunctional groups, such as aldehydes, ketones, esters, alkenes, alkoxygroups, cyano groups, amines, amides and N-oxides. In certainembodiments, the fluorinated organic compound contains a chiral centerthat is derived from the starting material. The stereochemistry at thechiral center may remain substantially unchanged (e.g., little to noracemization or epimerization of the chiral center occurs during thereaction). In the case of chiral aliphatic hydroxyls, thestereochemistry at the chiral center may be inverted. In certainembodiments, inversion is stereospecific. In certain embodiments,enantiomeric purity may fall by less than 5%. In certain embodiments,enantiomeric purity may fall by 5-10%. In certain embodiments,enantiomeric purity may fall by 10-20%. In certain embodiments,enantiomeric purity may fall by 20-30%.

In certain embodiments, the fluorinated organic compound is ¹⁹F labeled.In certain embodiments, the labeled organic compound is an imagingagent, such as an MRI imaging agents. In certain embodiments, thelabeled organic compound may be used as a probe, such as a biologicalNMR probes for use in in vivo NMR spectroscopy.

In certain embodiments, the fluorinated organic compound is ¹⁸F labeled.In certain embodiments, the ¹⁸F-labeled organic compound is an imagingagent, such as a PET imaging agent.

In certain embodiments, the fluorinated organic compound is a compoundhaving biological activity. In certain embodiments, the fluorinatedorganic compound is a compound with pharmacologic activity (i.e., bindsto a receptor or enzyme). Exemplary fluorinated organic compoundsinclude fluoro-estrone, fluoro-menthol, fluoro-cholesterol, andfluoro-testosterone. In certain embodiments, the fluorinated organiccompound is described in previous applications by the inventorsPCT/US2009/065339, published as WO 10/059943, PCT/US2010/020540,published as WO 10/081034, PCT/US2010/020544, published as WO/081036,PCT/US2010/041561, published as WO 11/006088, and U.S. application, U.S.Ser. No. 61/721,131, filed Nov. 1, 2012, and these documents areincorporated herein by reference.

Kits

The fluorination reagent used in the inventive methods described hereinmay be provided in a kit. The kit includes (a) the fluorination reagentuseful in the inventive method described herein (e.g., a compound ofFormulas (I), (II), or (VI)), and, optionally (b) informationalmaterial. The informational material can be descriptive, instructional,marketing or other material that relates to the methods described hereinand/or the use of the compounds for the methods described herein.

The informational material of the kits is not limited in its form. Inone embodiment, the informational material can include information aboutproduction of the fluorination reagent, molecular weight of thefluorination reagent, concentration, date of expiration, batch orproduction site information, and so forth. In one embodiment, theinformational material relates to methods for using the fluorinationreagent.

In certain embodiments, the informational material, e.g., instructions,is provided in printed matter, e.g., a printed text, drawing, and/orphotograph, e.g., a label or printed sheet. However, the informationalmaterial can also be provided in other formats, such as Braille,computer readable material, video recording, or audio recording. Inanother embodiment, the informational material of the kit is contactinformation, e.g., a physical address, email address, website, ortelephone number, where a user of the kit can obtain substantiveinformation about a fluorination reagent described herein and/or its usein the methods described herein. Of course, the informational materialcan also be provided in any combination of formats.

In certain embodiments, the components of the kit are stored under inertconditions (e.g., under nitrogen or another inert gas such as argon). Incertain embodiments, the components of the kit are stored underanhydrous conditions (e.g., with a desiccant). In certain embodiments,the components are stored in a light blocking container such as an ambervial.

The fluorination reagent described herein can be provided in any form,e.g., liquid, dried, or lyophilized form. It is preferred that thefluorination reagent described herein be substantially pure and/orsterile. When the fluorination reagent described herein is provided as adried form, reconstitution generally is by the addition of a suitablesolvent.

The kit can include one or more containers for the compositioncontaining the fluorination reagent described herein. In certainembodiments, the kit contains separate containers, dividers orcompartments for the composition and informational material. Forexample, the composition can be contained in a bottle, vial, or ampule,and the informational material can be contained in a plastic sleeve orpacket. In other embodiments, the separate elements of the kit arecontained within a single, undivided container. For example, thecomposition is contained in a bottle, vial or ampule that has attachedthereto the informational material in the form of a label. Thecontainers of the kits can be air tight, waterproof (e.g., impermeableto changes in moisture or evaporation), and/or light-tight.

Current reagents of Formula (I), (II), or (VI) will enable theautomation of all transformations described above. The described methodsare readily adaptable to the most widely available automated equipment.This will enable broad application to PET facilities throughout thecommunity without infrastructure investments. In certain embodiments,¹⁸F labeling with the inventive method is carried out in line with anrobotic reagent dispensing and weighing system such as a Tecan MCA96. Incertain embodiments, ¹⁸F labeling with the inventive method is performedin a parallel reactor system such as a Mettler Bohdan Miniblock. Incertain embodiments, ¹⁸F labeling with the inventive method is performedin line with an automatic purification and analytical system such as aWaters AutoPurification HPLC/MS.

EXAMPLES Materials and Methods

Solvents other than methanol were dried by passage through alumina.Except as indicated otherwise, reactions were magnetically stirred andmonitored by thin layer chromatography (TLC) using EMD TLC platespre-coated with 250 μm thickness silica gel 60 F254 plates andvisualized by fluorescence quenching under UV light. In addition, TLCplates were stained using ceric ammonium molybdate or potassiumpermanganate stain. Flash chromatography was performed on DynamicAdsorbents Silica Gel 40-63 μm particle size or Whatman Silica Gel 60 μmparticle size using a forced flow of eluent at 0.3-0.5 bar pressure.Concentration under reduced pressure was performed by rotary evaporationat 25-30° C. at appropriate pressure. Purified compounds were furtherdried under high vacuum (0.01-0.05 Torr). NMR spectra were recorded on aVarian Mercury 400 (400 MHz for ¹H, 100 MHz for ¹³C, 375 MHz for ¹⁹F,and 126 MHz for ³¹P acquisitions), Unity/Inova 500 (500 MHz for ¹H, 125MHz for ¹³C acquisitions), or Unity/Inova 600 (600 MHz for ¹Hacquisitions) spectrometer. ¹³C NMR spectra are recorded 1H decoupled.¹⁹F NMR spectra are recorded 1H coupled. Chemical shifts are reported inppm with the solvent resonance as the internal standard. Data isreported as follows: s=singlet, d=doublet, t=triplet, q=quartet,h=heptet, m=multiplet, br=broad; coupling constants in Hz; integration.High-resolution mass spectra were obtained on Jeol AX-505 or SX-102spectrometers at the Harvard University Mass Spectrometry Facilities.Sodium hydroxide was purchased from Mallinckrodt Chemicals, Molecularsieves 3 Å were purchased from EMD Chemicals and finely grinded anddried at 130° C. overnight prior to use. NMR spectroscopic data of knowncompounds correspond to the data given in the appropriate references.Pyridine and triethylamine were distilled over calcium hydride. NMRspectroscopic data of known compounds correspond to the data given inthe appropriate references.

Example 1. Preparation of I-c

To 1,3-bis(2,6-diisopropylphenyl)-1,3-dihydro-2H-imidazol-2-one (2.00 g,4.93 mmol, 1.00 equiv) in dichloromethane (10 mL) at 23° C. was addedtriflic acid (435 μL, 4.93 mmol, 1.00 equiv). The reaction mixture wasstirred for 1 hour before 50 ml hexanes were added to afford a whiteprecipitate. The solids were collected by filtration and washed withhexanes (10 mL) and then dried under vacuum to afford 2.68 g of thetitle compound as a white solid (97% yield). X-ray quality crystals weregrown by storing a concentrated solution of (I-c) in CDCl₃ at 23° C.giving colorless crystals after 24 hours.

mp: 180° C. (decomp). NMR spectroscopy: 1H-NMR (400 MHz, CDCl₃, 23° C.,δ): 8.22 (broad, 1H), 7.52 (t, J=7.8 Hz, 2H), 7.33 (d, J=7.8 Hz, 4H),6.73 (s, 2H), 2.66 (sept, J=7.0 Hz, 4H), 1.27 (d, J=4.3 Hz, 24H), 1.25(d, J=3.9 Hz, 12H). 13C-NMR (125 MHz, CDCl₃, 23° C., δ): 149.0, 145.8,131.4, 127.9, 124.9, 124.4, 117.5, 28.9, 23.5, 23.2. 19F-NMR (375 MHz,CDCl₃, 23° C., δ): −74.4 (s). FT-IR Spectroscopy (solid, cm−1): 3453,2963, 2931, 2871, 1676, 1622, 1515, 1458, 1302, 1175. Anal: calcd forC28H37F3N2O4S: C, 60.63; H, 6.72; N, 5.05; F, 10.28. found: C, 60.60; H,6.56; N, 5.01; F, 9.92.

To 1,3-bis(2,6-diisopropylphenyl)-1,3-dihydro-2H-imidazol-2-one (10.0 g,24.7 mmol, 1.00 equiv) in dichloromethane (35 mL) at −78° C. was addedtriflic anhydride (4.2 mL, 24.7 mmol, 1.00 equiv). The reaction mixturewas stirred for 5 min before 200 ml hexanes were added to afford a whiteprecipitate. The solids were collected by filtration and washed withhexanes (20 mL) and then dried under vacuum to afford 12.8 g of thetitle compound as a white solid (94% yield).

Example 2. X-Ray Structure of I-c

I-c was crystallized as colorless plates by slow evaporation of aconcentrated CDCl₃ solution. A 0.4×0.3×0.1 mm crystal was selected andmounted on a nylon loop using Paratone-N oil, and transferred to aBruker APEX II CCD diffractometer (MoK radiation, λ=0.71073 Å) equippedwith an Oxford Cryosystems nitrogen flow apparatus. The sample was heldat 150 K during the data collection. The collection method involved 0.5°scans in ω at 28° in 2θ. Data integration down to 0.82 Å resolution wascarried out using SAINT V7.46 A (Bruker diffractometer, 2009) withreflection spot size optimisation. Absorption corrections were made withthe program SADABS (Bruker diffractometer, 2009). The structure wassolved by the direct methods procedure and refined by least-squaresmethods against F² using SHELXS-97 and SHELXL-97 (Sheldrick, 2008).Non-hydrogen atoms were refined anisotropically, and hydrogen atoms wereallowed to ride on the respective atoms. Restraints on bond lengths andconstraints of the atomic displacement parameters on each pair ofdisorder fragments (SADI and EADP instructions of SHELXL97), asnecessary, have been applied for the disorder refinement. Crystal data,details of data collection and refinement, and selected geometricparameters are given in the tables below. Graphics were produced usingthe CystalMaker 8.6 software program (©1994-2012 CrystalMaker SoftwareLtd.) (see FIGS. 4 and 5 for X-ray structure images).

Example 3. General ¹⁸F Radiolabeling Procedure with I-c

No-carrier-added [¹⁸F]fluoride was produced from water 97% enriched in¹⁸O (Sigma-Aldrich®) by the nuclear reaction ¹⁸O(p,n)¹⁸F using a SiemensEclipse HP cyclotron and a silver-bodied target at MGH Athinoula A.Martinos Center for Biomedical Imaging. The produced [¹⁸F]fluoride inwater was transferred from the cyclotron target by helium push. In theanalysis of the ¹⁸F-labeled compounds, isotopically unmodified referencesubstances were used for identification. Radioactivity was measured in aCapintec, Inc. CRC-25PET ion chamber. Solvents and reagents forradiochemical experiments: Acetonitrile, extra dry, (AcroSeal®) anddichloroethane, extra dry, (AcroSeal®) was purchased from Acros® andused as received. Water was obtained from a Millipore Milli-Q IntegralWater Purification System. 18-crown-6 was sublimed. Potassium carbonate(≥99.99%) was purchased from Sigma-Aldrich® and used as received.

[¹⁸F]Fluoride solution obtained from a cyclotron was loaded onto aMacherey-Nagel SPE Chromafix 30-PS-HCO₃ cartridge that had beenpreviously washed with 2.0 mL of 5.0 mg/mL K₂CO₃ in Millipore Milli-Qwater and then 20 mL of Millipore Milli-Q water. After loading, thecartridge was washed with 2 mL of Millipore Milli-Q water. [¹⁸F]Fluoridewas eluted with 0.5 mL of a 5.0 mg/mL K₂CO₃ in Millipore Milli-Q watersolution. The solution was diluted with 2.0 mL of acetonitrile providing2.5 mL of 4:1 MeCN:H₂O solution containing 1.0 mg/mL K₂CO₃. Thissolution was then put in a conical vial and 0.50 mL of a stock solutioncontaining 18-crown-6 (13 mg/mL MeCN) was then added. The solution wasevaporated at 108° C. with a constant nitrogen gas stream. At dryness,0.5 mL of acetonitrile was added and evaporated at 108° C. with aconstant nitrogen gas stream. Another 0.5 mL of acetonitrile was addedand evaporated at 108° C. with a constant nitrogen gas stream to leave awhite precipitate around the bottom and sides of the vial. The vial waspurged with nitrogen, and sealed with a cap fitted with a septum. 0.3 mLof a solution of (I-c) (5 mg, 9.0×10⁻³ mmol) and the phenol of interest(10 mg) was added and the conical vial was sonicated for 5 secondsbefore it was heated for 15 minutes.

After the reaction mixture was allowed to cool to 23° C., a capillarytube was used to spot the solution on a silica gel TLC plate. The TLCplate was eluted and the TLC plate was scanned with a Bioscan AR-2000Radio TLC Imaging Scanner to determine [¹⁸F]fluoride incorporation intothe aryl fluoride product. Radiolabeled products were indentifiedthrough co-injection with an authentic standard on radio-HPLC.

Example 4. Radiolabeling of Estrone Using I-c

Following azeotropic drying of ¹⁸F-fluoride (see general experimentalsection), 5 mg (I-c) and 10 mg estrone dissolved in dichloroethane (0.3ml) were added and the reaction mixture was heated to 110° C. for 15minutes. After the reaction mixture was allowed to cool to 23° C., acapillary tube was used to spot the solution on a silica gel TLC plateand was eluted with a 4:1 (v:v) hexanes:ethyl acetate (see FIG. 6A).

Example 5. Radiolabeling of Testosterone Using (I-c)

Following azeotropic drying of ¹⁸F-fluoride (see general experimentalsection), 5 mg (I-c) and 10 mg testosterone dissolved in dichloroethane(0.3 ml) were added and the reaction mixture was heated to 110° C. for15 minutes. After the reaction mixture was allowed to cool to 23° C., acapillary tube was used to spot the solution on a silica gel TLC plateand was eluted with a 4:1 (v:v) hexanes:ethyl acetate (see FIG. 6B).

Example 5. Radiolabeling of Menthol Using I-c

Following azeotropic drying of ¹⁸F-fluoride (see general experimentalsection), 5 mg (I-c) and 10 mg menthol dissolved in dichloroethane (0.3ml) were added and the reaction mixture was heated to 110° C. for 15minutes. After the reaction mixture was allowed to cool to 23° C., acapillary tube was used to spot the solution on a silica gel TLC plateand was eluted with a 4:1 (v:v) hexanes:ethyl acetate (see FIG. 6C).

Other Substrates for Fluorination with I-c. Decay-CorrectedRadiochemical Conversion for the Radiofluorination with I-c CurrentlyRange from 4% to 26%.

Synthesis of Thiol Containing Derivatives of Formula (I).

Example 6. Use of Anion Exchange on Chloro Uronium Intermediates forFluorination of Organic Substrates

¹⁸F-fluoride is prepared as a solution in water, which is subsequentlytrapped on an ion exchange cartridge and typically eluted with aninorganic base to prepare the ¹⁸F salt of choice as an aqueous solution,which is usually azeotropically dried in the presence of a chelatingagent. In order to introduce ¹⁸F as the counteranion of the uroniumintermediate, a solution of uronium precursor in an aqueous dioxanesolution is used for elution of the activity in a reaction vial, whichis capped and heated to 110° C. for 5 min. The radiolabeling procedureis insensitive to air and moisture and the radiolabeled product can beconveniently separated from the reaction precursor. A wide variety offunctional groups is tolerated and arenes bearing electron-donating orelectron-withdrawing substituents as well as heterocycles undergoradiofluorination in high radiochemical conversion.

Other Embodiments

In the claims articles such as “a,” “an,” and “the” may mean one or morethan one unless indicated to the contrary or otherwise evident from thecontext. Claims or descriptions that include “or” between one or moremembers of a group are considered satisfied if one, more than one, orall of the group members are present in, employed in, or otherwiserelevant to a given product or process unless indicated to the contraryor otherwise evident from the context. The invention includesembodiments in which exactly one member of the group is present in,employed in, or otherwise relevant to a given product or process. Theinvention includes embodiments in which more than one, or all of thegroup members are present in, employed in, or otherwise relevant to agiven product or process.

Furthermore, the invention encompasses all variations, combinations, andpermutations in which one or more limitations, elements, clauses, anddescriptive terms from one or more of the listed claims is introducedinto another claim. For example, any claim that is dependent on anotherclaim can be modified to include one or more limitations found in anyother claim that is dependent on the same base claim. Where elements arepresented as lists, e.g., in Markush group format, each subgroup of theelements is also disclosed, and any element(s) can be removed from thegroup. It should it be understood that, in general, where the invention,or aspects of the invention, is/are referred to as comprising particularelements and/or features, certain embodiments of the invention oraspects of the invention consist, or consist essentially of, suchelements and/or features. For purposes of simplicity, those embodimentshave not been specifically set forth in haec verba herein. It is alsonoted that the terms “comprising” and “containing” are intended to beopen and permits the inclusion of additional elements or steps. Whereranges are given, endpoints are included. Furthermore, unless otherwiseindicated or otherwise evident from the context and understanding of oneof ordinary skill in the art, values that are expressed as ranges canassume any specific value or sub-range within the stated ranges indifferent embodiments of the invention, to the tenth of the unit of thelower limit of the range, unless the context clearly dictates otherwise.

This application refers to various issued patents, published patentapplications, journal articles, and other publications, all of which areincorporated herein by reference. If there is a conflict between any ofthe incorporated references and the instant specification, thespecification shall control. In addition, any particular embodiment ofthe present invention that falls within the prior art may be explicitlyexcluded from any one or more of the claims. Because such embodimentsare deemed to be known to one of ordinary skill in the art, they may beexcluded even if the exclusion is not set forth explicitly herein. Anyparticular embodiment of the invention can be excluded from any claim,for any reason, whether or not related to the existence of prior art.

Those skilled in the art will recognize or be able to ascertain using nomore than routine experimentation many equivalents to the specificembodiments described herein. The scope of the present embodimentsdescribed herein is not intended to be limited to the above Description,but rather is as set forth in the appended claims. Those of ordinaryskill in the art will appreciate that various changes and modificationsto this description may be made without departing from the spirit orscope of the present invention, as defined in the following claims.

What is claimed is:
 1. A compound of Formula (I):

wherein D is oxygen; A is hydrogen, LiX, MgX₂, ScX₃, ScR⁶ ₃YX₃, YR⁶ ₃,BR⁶ ₃, BX₃, TiX₄, TiR⁶ ₄, ZrX₄, ZrR⁶ ₄, FeX₃, FeR⁶ ₃, ZnX₂, ZnR⁶ ₂,AlX₃, AlR⁶ ₃, InX₃, InR⁶ ₃, SiX₄, SiR⁶ ₄, SnX₂, SnR⁶ ₂, SnX₄, SnR⁶ ₄,BiX₃, or BiR⁶ ₃; each occurrence of R⁶ is independently C₁₋₆ alkyl,—OR⁷, C₆₋₁₀ aryl, C₆₋₁₀ aralkyl, 5-10 membered heteroaryl, 5-10 memberedheteroaralkyl, 4-10 membered heterocyclyl, 4-10 memberedheterocyclylalkyl, 3-10 membered carbocyclyl, or 3-10 memberedcarbocyclylalkyl, wherein each of C₁₋₆ alkyl, C₆₋₁₀ aryl, C₆₋₁₀ aralkyl,5-10 membered heteroaryl, 5-10 membered heteroaralkyl, 4-10 memberedheterocyclyl, 4-10 membered heterocyclylalkyl, 3-10 memberedcarbocyclyl, and 3-10 membered carbocyclylalkyl is independentlyoptionally substituted with 0 to 5 occurrences of R⁵; each occurrence ofX is independently halogen or Q^(−t); Q^(−t) is an anion; R¹ and R² areindependently selected from the group consisting of C₁₋₆ alkyl, C₆₋₁₀aryl, C₆₋₁₀ aralkyl, 5-10 membered heteroaryl, 5-10 memberedheteroaralkyl, 4-10 membered heterocyclyl, 4-10 memberedheterocyclylalkyl, 3-10 membered carbocyclyl, and 3-10 memberedcarbocyclylalkyl, each of which is independently optionally substitutedwith 0 to 5 occurrences of R⁵; R³ and R⁴ are independently selected fromthe group consisting of hydrogen, unsubstituted C₁₋₆ alkyl, optionallysubstituted C₂₋₆ alkenyl, optionally substituted C₂₋₆ alkynyl, nitro,cyano, halo, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, optionally substituted C₆₋₁₀aryl, optionally substituted C₆₋₁₀ aralkyl, optionally substituted 5-10membered heteroaryl, optionally substituted 4-10 membered heterocyclyl,optionally substituted 3-10 membered carbocyclyl, optionally substituted4-10 membered heterocyclylalkyl, acyl, —NH₂, —NHR⁷, —N(R⁷)₂, —OH, —SH,—SO₂R⁷, —SOR⁷, —SO₂N(R⁷)₂, and —SR⁷; each occurrence of R⁷ isindependently selected from the group consisting of hydrogen, acyl,optionally substituted aliphatic, optionally substituted carbocyclyl,optionally substituted heterocyclyl, optionally substituted aryl, andoptionally substituted heteroaryl, or two R⁷ groups are taken togetherwith their intervening atoms to form an optionally substitutedheterocyclic ring; each occurrence of R⁵ is independently selected fromthe group consisting of halo, optionally substituted C₁₋₆ alkyl,optionally substituted C₂₋₆ alkenyl, optionally substituted C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, optionally substituted C₆₋₁₀ aryl,optionally substituted 5-10 membered heteroaryl, optionally substituted4-10 membered heterocyclyl, optionally substituted 3-10 memberedcarbocyclyl, nitro, cyano, acyl, —NH₂, —NHR⁷, —N(R⁷)₂, —OH, —SH, —SO₂R⁷,—SOR⁷, —SO₂N(R⁷)₂, and —SR⁷; t is the anion charge number and is 1, 2,or 3; v is 0, 1, 2, or 3; and m is 1, 2, 3, 4, or 5; provided that thecompound is electrically neutral.
 2. The compound of claim 1, wherein R¹and R² are independently C₆₋₁₀ aryl, optionally substituted with 0 to 5occurrences of R⁵.
 3. The compound of claim 1, wherein the compound isof Formula (I-a):


4. The compound of claim 1, wherein the compound is of Formula (I-b):


5. The compound of claim 3, wherein A is hydrogen, m is 1, t is 1, and vis
 1. 6. The compound of claim 1, wherein both R³ and R⁴ are hydrogen.7. The compound of claim 1, wherein the compound is of Formula (I-c):


8. The compound of claim 1, wherein Q^(−t) is a halide,trifluoroacetate, trichloroacetate, NO₂ ⁻, NO₃ ⁻, H₂PO₄ ⁻, PF₆ ⁻, HF²⁻,HSO₄ ⁻, SbF₆ ⁻, ClO₄ ⁻, SO₄ ⁻², (R⁶)SO₃ ⁻, OTf⁻, OTs⁻, ONf⁻, ONs⁻, BF₄⁻, or B(R⁶)₄ ⁻.
 9. The compound of claim 1, wherein A is LiX, MgX₂,ScX₃, ScR⁶ ₃YR⁶ ₃, BR⁶ ₃, BX₃, TiX₄, TiR⁶ ₄, ZrX₄, ZrR⁶ ₄, FeX₃, FeR⁶ ₃,ZnX₂, ZnR⁶ ₂, AlX₃, AlR⁶ ₃, InX₃, InR⁶ ₃, SiX₄, SiR⁶ ₄, SnX₂, SnR⁶ ₂,SnX₄, SnR⁶ ₄, BiX₃, or BiR⁶ ₃.
 10. A compound of Formula (II) or (II′):

wherein: S is an organic substrate; Q^(⊖) is Cl⁻, Br⁻, or NO₃ ⁻; Q^(2⊖)is SO₄ ²⁻; R¹ and R² are independently selected from the groupconsisting of C₁₋₆ alkyl, C₆₋₁₀ aryl, C₆₋₁₀ aralkyl, 5-10 memberedheteroaryl, 5-10 membered heteroaralkyl, 4-10 membered heterocyclyl,4-10 membered heterocyclylalkyl, 3-10 membered carbocyclyl, and 3-10membered carbocyclylalkyl, each of which is independently optionallysubstituted with 0 to 5 occurrences of R⁵; R³ and R⁴ are independentlyselected from the group consisting of hydrogen, optionally substitutedC₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl, optionally substitutedC₂₋₆ alkynyl, nitro, cyano, halo, C₁₋₆ haloalkyl, C₁₋₆ alkoxy,optionally substituted C₆₋₁₀ aryl, optionally substituted C₆₋₁₀ aralkyl,optionally substituted 5-10 membered heteroaryl, optionally substituted4-10 membered heterocyclyl, optionally substituted 3-10 memberedcarbocyclyl, optionally substituted 4-10 membered heterocyclylalkyl,acyl, —NH₂, —NHR⁷, —N(R⁷)₂, —OH, —SH, —SO₂R⁷, —SOR⁷, —SO₂N(R⁷)₂, and—SR⁷; each occurrence of R⁷ is independently selected from the groupconsisting of hydrogen, acyl, optionally substituted aliphatic,optionally substituted carbocyclyl, optionally substituted heterocyclyl,optionally substituted aryl, and optionally substituted heteroaryl, ortwo R⁷ groups are taken together with their intervening atoms to form anoptionally substituted heterocyclic ring; and each occurrence of R⁵ isindependently selected from the group consisting of halo, optionallysubstituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl, optionallysubstituted C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, optionallysubstituted C₆₋₁₀ aryl, optionally substituted 5-10 membered heteroaryl,optionally substituted 4-10 membered heterocyclyl, optionallysubstituted 3-10 membered carbocyclyl, nitro, cyano, acyl, —NH₂, —NHR⁷,—N(R⁷)₂, —OH, —SH, —SO₂R⁷, —SOR⁷, —SO₂N(R⁷)₂, and —SR⁷.
 11. A compoundof Formula (V):

wherein: S is an organic substrate; R¹ and R² are independently selectedfrom the group consisting of C₁₋₆ alkyl, C₆₋₁₀ aryl, C₆₋₁₀ aralkyl, 5-10membered heteroaryl, 5-10 membered heteroaralkyl, 4-10 memberedheterocyclyl, 4-10 membered heterocyclylalkyl, 3-10 memberedcarbocyclyl, and 3-10 membered carbocyclylalkyl, each of which isindependently optionally substituted with 0 to 5 occurrences of R⁵; R³and R⁴ are independently selected from the group consisting of hydrogen,optionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl,optionally substituted C₂₋₆ alkynyl, nitro, cyano, halo, C₁₋₆ haloalkyl,C₁₋₆ alkoxy, optionally substituted C₆₋₁₀ aryl, optionally substitutedC₆₋₁₀ aralkyl, optionally substituted 5-10 membered heteroaryl,optionally substituted 4-10 membered heterocyclyl, optionallysubstituted 3-10 membered carbocyclyl, optionally substituted 4-10membered heterocyclylalkyl, acyl, —NH₂, —NHR⁷, —N(R⁷)₂, —OH, —SH,—SO₂R⁷, —SOR⁷, —SO₂N(R⁷)₂, and —SR⁷; each occurrence of R⁷ isindependently selected from the group consisting of hydrogen, acyl,optionally substituted aliphatic, optionally substituted carbocyclyl,optionally substituted heterocyclyl, optionally substituted aryl, andoptionally substituted heteroaryl, or two R⁷ groups are taken togetherwith their intervening atoms to form an optionally substitutedheterocyclic ring; and R⁵ is independently selected from the groupconsisting of halo, optionally substituted C₁₋₆ alkyl, optionallysubstituted C₂₋₆ alkenyl, optionally substituted C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₁₋₆ alkoxy, optionally substituted C₆₋₁₀ aryl, optionallysubstituted 5-10 membered heteroaryl, optionally substituted 4-10membered heterocyclyl, optionally substituted 3-10 membered carbocyclyl,nitro, cyano, acyl, —NH₂, —NHR⁷, —N(R⁷)₂, —OH, —SH, —SO₂R⁷, —SOR⁷,—SO₂N(R⁷)₂, and —SR⁷.
 12. The compound of claim 10, wherein the compoundis of Formula (VI):

wherein: each occurrence of R⁸ is independently selected from the groupconsisting of optionally substituted C₁₋₆ alkyl, optionally substitutedC₂₋₆ alkenyl, optionally substituted C₂₋₆ alkynyl, nitro, cyano, halo,C₁₋₆ haloalkyl, C₁₋₆ alkoxy, optionally substituted C₆₋₁₀ aryl,optionally substituted C₆₋₁₀ aralkyl, optionally substituted 5-10membered heteroaryl, optionally substituted 4-10 membered heterocyclyl,optionally substituted 3-10 membered carbocyclyl, optionally substituted4-10 membered heterocyclylalkyl, acyl, —N(R^(8a))₂, —OR⁸a, —CO₂R^(8a),—SO₂R^(8a), —SOR^(8a), —SO₂N(R^(8a))₂, and —SR^(8a); each occurrence ofR⁹ is independently selected from the group consisting of optionallysubstituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl, optionallysubstituted C₂₋₆ alkynyl, nitro, cyano, halo, C₁₋₆ haloalkyl, C₁₋₆alkoxy, optionally substituted C₆₋₁₀ aryl, optionally substituted C₆₋₁₀aralkyl, optionally substituted 5-10 membered heteroaryl, optionallysubstituted 4-10 membered heterocyclyl, optionally substituted 3-10membered carbocyclyl, optionally substituted 4-10 memberedheterocyclylalkyl, acyl, —N(R^(9a))₂, —OR^(9a), —CO₂R^(9a), —SO₂R^(9a),—SOR^(9a), —SO₂N(R^(9a))₂, and —SR^(9a); each occurrence of R^(8a) orR^(9a) is independently selected from the group consisting of hydrogen,acyl, optionally substituted aliphatic, optionally substitutedcarbocyclyl, optionally substituted heterocyclyl, optionally substitutedaryl, and optionally substituted heteroaryl, or two R^(8a) or R^(9a)groups are taken together with their intervening atoms to form anoptionally substituted heterocyclic ring; and p is 0, 1, 2, or
 3. 13. Areaction mixture comprising a compound of Formula (I) of claim 1 and afluorine source.
 14. The compound of claim 10, wherein S is optionallysubstituted aryl or optionally substituted heteroaryl.
 15. The compoundof claim 10, wherein compound is of Formula (II):

wherein Q^(⊖) is Cl⁻.
 16. The compound of claim 10, wherein R¹ and R²are independently C₆₋₁₀ aryl, optionally substituted with 0 to 5occurrences of R⁵.
 17. The compound of claim 10, wherein R³ and R⁴ arehydrogen.
 18. The compound of claim 10, wherein the compound is ofFormula (II-a):


19. The compound of claim 10, wherein the compound is of Formula (II-b):


20. The compound of claim 10, wherein the compound is of Formula (II-h):


21. The compound of claim 10, wherein the compound is of Formula (II-e):


22. The compound of claim 10, wherein: the compound is of Formula(II-e):

and S is optionally substituted aryl or optionally substitutedheteroaryl.
 23. The compound of claim 10, wherein: the compound is ofFormula (II-e):

and S is:


24. The compound of claim 11, wherein S is optionally substituted arylor optionally substituted heteroaryl.
 25. The compound of claim 11,wherein R¹ and R² are independently C₆₋₁₀ aryl, optionally substitutedwith 0 to 5 occurrences of R⁵.
 26. The compound of claim 11, wherein R³and R⁴ are hydrogen.
 27. A method of replacing a hydroxyl group on anorganic compound with a fluorine atom, the method comprising contactinga compound of Formula (I) of claim 1:

with an organic compound under conditions sufficient to replace thehydroxyl group of the organic compound with a fluorine atom, wherein D,A, Q^(−t), R¹, R², R³, R⁴, t, v, and m are as defined in claim
 1. 28. Amethod of replacing a hydroxyl group on an organic compound with afluorine atom, the method comprising exchanging Q^(⊖) of a compound ofFormula (II) of claim 10 or exchanging Q^(2⊖) of Formula (II′) of claim10:

with a fluoride or HF₂ anion, wherein S, Q^(⊖), Q^(2⊖), R¹, R², R³, andR⁴ are as defined in claim
 10. 29. A method of producing a compound ofFormula (II) or (II′) of claim 10:

the method comprising contacting a compound of Formula (VI) or (VI′):

with a hydroxyl group-containing organic substrate and exchanging

wherein: S, Q^(⊖), Q^(2⊖), R¹, R², R³, and R⁴ are as defined in claim10; each occurrence of R⁸ is independently selected from the groupconsisting of optionally substituted C₁₋₆ alkyl, optionally substitutedC₂₋₆ alkenyl, optionally substituted C₂₋₆ alkynyl, nitro, cyano, halo,C₁₋₆ haloalkyl, C₁₋₆ alkoxy, optionally substituted C₆₋₁₀ aryl,optionally substituted C₆₋₁₀ aralkyl, optionally substituted 5-10membered heteroaryl, optionally substituted 4-10 membered heterocyclyl,optionally substituted 3-10 membered carbocyclyl, optionally substituted4-10 membered heterocyclylalkyl, acyl, —N(R^(8a))₂, —OR^(8a),—CO₂R^(8a), —SO₂R^(8a), —SOR^(8a), —SO₂N(R^(8a))₂, and —SR^(8a); eachoccurrence of R⁹ is independently selected from the group consisting ofoptionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl,optionally substituted C₂₋₆ alkynyl, nitro, cyano, halo, C₁₋₆ haloalkyl,C₁₋₆ alkoxy, optionally substituted C₆₋₁₀ aryl, optionally substitutedC₆₋₁₀ aralkyl, optionally substituted 5-10 membered heteroaryl,optionally substituted 4-10 membered heterocyclyl, optionallysubstituted 3-10 membered carbocyclyl, optionally substituted 4-10membered heterocyclylalkyl, acyl, —N(R^(9a))₂, —OR^(9a), —CO₂R^(9a),—SO₂R^(9a), —SOR^(9a), —SO₂N(R^(9a))₂, and —SR^(9a); each occurrence ofR^(8a) and R^(9a) is independently selected from the group consisting ofhydrogen, acyl, optionally substituted aliphatic, optionally substitutedcarbocyclyl, optionally substituted heterocyclyl, optionally substitutedaryl, and optionally substituted heteroaryl, or two R^(8a) or R^(9a)groups are taken together with their intervening atoms to form anoptionally substituted heterocyclic ring; and p is 0, 1, 2, or
 3. 30. Amethod of producing a compound of Formula (I) of claim 1, the methodcomprising reacting a compound of Formula (I-e):

with a Brønsted acid, a Lewis acid, or an acid anhydride to produce thecompound of Formula (I), wherein the Lewis acid is LiX, MgX₂, ScX₃, ScR⁶₃YX₃, YR⁶ ₃, BR⁶ ₃, BX₃, TiX₄, TiR⁶ ₄, ZrX₄, ZrR⁶ ₄, FeX₃, FeR⁶ ₃, ZnX₂,ZnR⁶ ₂, AlX₃, AlR⁶ ₃, InX₃, InR⁶ ₃, SiX₄, SiR⁶ ₄, SnX₂, SnR⁶ ₂, SnX₄,SnR⁶ ₄, BiX₃, or BiR⁶ ₃; and X, R⁶, D, R¹, R², R³, and R⁴ are as definedin claim 1.